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An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review

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Abstract

RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS’s structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein’s role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS–effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field’s future.

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References

  1. Saad II, Saha SB, Thomas G (2014) The RAS subfamily evolution—tracing evolution for its utmost exploitation. Bioinformation 10:1–6

    Article  Google Scholar 

  2. Qu L, Pan C, He S-M, Lang B, Gao G-D, Wang X-L, Wang Y (2019) The ras superfamily of small gtpases in non-neoplastic cerebral diseases. Front Mol Neurosci 12:1–21

    Article  Google Scholar 

  3. Nair A, Saha B (2023) Regulation of Ras-GTPase signaling and localization by post-translational modifications. Kinases and Phosphatases 1:97–116

    Article  Google Scholar 

  4. Xiao H, Wang G, Zhao M, Shuai W, Ouyang L, Sun Q (2023) Ras superfamily GTPase activating proteins in cancer: potential therapeutic targets? Eur J Med Chem:1–19.

  5. Khalid E, Chang JP (2023) Small GTPase control of pituitary hormone secretion: evidence from studies in the goldfish (Carassius auratus) neuroendocrine model. Gen Comp Endocrinol 339:1–12

    Article  Google Scholar 

  6. van Dam TJ, Bos J, Snel B (2011) Evolution of the Ras-like small GTPases and their regulators. Small GTPases 2:1–14

    Google Scholar 

  7. Goitre L, Trapani E, Trabalzini L, Retta SF (2014) The Ras superfamily of small GTPases: the unlocked secrets. Ras signaling: methods and protocols. Humana Press, pp 1–18

    Google Scholar 

  8. Parker JA, Mattos C (2018) The K-Ras, N-Ras, and H-Ras isoforms: unique conformational preferences and implications for targeting oncogenic mutants. Cold Spring Harb Perspect Med 8:1–15

    Article  CAS  Google Scholar 

  9. Johnson CW, Reid D, Parker JA, Salter S, Knihtila R, Kuzmic P, Mattos C (2017) The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects. J Biol Chem 292:12981–12993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aran V, Domingues PM, de Macedo FC, de Sousa CAM, Montella TC, de Souza Accioly MT, Ferreira CG (2018) A cross-sectional study examining the expression of splice variants K-RAS4A and K-RAS4B in advanced non-small-cell lung cancer patients. Lung Cancer 116:7–14

    Article  PubMed  Google Scholar 

  11. Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of Ras mutations in cancer. Can Res 72:2457–2467

    Article  CAS  Google Scholar 

  12. Nuevo-Tapioles C, Philips MR (2022) The role of KRAS splice variants in cancer biology. Front Cell Dev Biol 10:1–9

    Article  Google Scholar 

  13. Jiajun Y, Jiancheng H (2023) Target hyperactive ERK signaling for cancer therapy. Handbook of cancer and immunology. Springer, pp 1–39

    Google Scholar 

  14. Sperlich B, Kapoor S, Waldmann H, Winter R, Weise K (2016) Regulation of K-Ras4B membrane binding by calmodulin. Biophys J 111:113–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tsai FD, Lopes MS, Zhou M, Court H, Ponce O, Fiordalisi JJ, Gierut JJ, Cox AD, Haigis KM, Philips MR (2015) K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci 112:779–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Asati V, Mahapatra DK, Bharti SK (2016) PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem 109:314–341

    Article  CAS  PubMed  Google Scholar 

  17. Weber SM, Carroll SL (2021) The role of R-Ras proteins in normal and pathologic migration and morphologic change. Am J Pathol 191:1499–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS (2023) An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 322:1–18

    Article  Google Scholar 

  19. Doghish AS, Moustafa HAM, Elballal MS, Sallam A-AM, El-Dakroury WA, Mageed SSA, Elesawy AE, Abdelmaksoud NM, Shahin RK, Midan HM (2023) The potential role of miRNAs in the pathogenesis of testicular germ cell tumors—a focus on signaling pathways interplay. Pathol—Res Pract 248:1–13

    Google Scholar 

  20. Hobbs GA, Der CJ, Rossman KL (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129:1287–1292

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Radoux-Mergault A, Oberhauser L, Aureli S, Gervasio FL, Stoeber M (2023) Subcellular location defines GPCR signal transduction. Sci Adv 9:1–17

    Article  Google Scholar 

  22. Yang Y, Liu J-J (2022) Structural LTP: Signal transduction, actin cytoskeleton reorganization, and membrane remodeling of dendritic spines. Curr Opin Neurobiol 74:1–9

    Article  Google Scholar 

  23. Lu H, Martí J (2022) Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRas-4B proteins at zwitterionic model cell membranes. Nanoscale 14:3148–3158

    Article  CAS  PubMed  Google Scholar 

  24. Zhou Y, Prakash P, Gorfe AA, Hancock JF (2018) Ras and the plasma membrane: a complicated relationship. Cold Spring Harb Perspect Med 8:1–14

    Article  Google Scholar 

  25. Samad A, Khurshid B, Mahmood A, Rehman AU, Khalid A, Abdalla AN, Algarni AS, Wadood A (2023) Identification of novel peptide inhibitors for oncogenic KRAS G12D as therapeutic options using mutagenesis-based remodeling and MD simulations. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2023.2192298

    Article  PubMed  Google Scholar 

  26. Liu C, Ye D, Yang H, Chen X, Su Z, Li X, Ding M, Liu Y (2023) RAS-targeted cancer therapy: advances in drugging specific mutations. MedComm 4:1–27

    Article  Google Scholar 

  27. Tesfamariam B (2023) Targeting Rho kinase to restore endothelial barrier function following vascular scaffold implantation. Drug Discov Today 28:1–8

    Article  Google Scholar 

  28. Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Aktories K (2023) From signal transduction to protein toxins—a narrative review about milestones on the research route of C. difficile toxins. Naunyn-Schmiedeberg’s Arch Pharmacol 396:173–190

    Article  CAS  Google Scholar 

  30. Rathod LS, Dabhade PS, Mokale SN (2023) Recent progress in targeting KRAS mutant cancers with covalent G12C-specific inhibitors. Drug Discov Today 28:1–11

    Article  Google Scholar 

  31. Cherfils J, Zeghouf M (2013) Regulation of small gtpases by gefs, gaps, and gdis. Physiol Rev 93:269–309

    Article  CAS  PubMed  Google Scholar 

  32. Asati V, Mahapatra DK, Bharti SK (2017) K-Ras and its inhibitors towards personalized cancer treatment: pharmacological and structural perspectives. Eur J Med Chem 125:299–314

    Article  CAS  PubMed  Google Scholar 

  33. Akagi K, Uchibori R, Yamaguchi K, Kurosawa K, Tanaka Y, Kozu T (2007) Characterization of a novel oncogenic K-Ras mutation in colon cancer. Biochem Biophys Res Commun 352:728–732

    Article  CAS  PubMed  Google Scholar 

  34. Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304

    Article  CAS  PubMed  Google Scholar 

  35. Pierre S, Coumoul X (2011) Understanding SOS (son of sevenless). Biochem Pharmacol 82:1049–1056

    Article  CAS  PubMed  Google Scholar 

  36. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877

    Article  CAS  PubMed  Google Scholar 

  37. Eva A, Aaronson SA (1985) Isolation of a new human oncogene from a diffuse B-cell lymphoma. Nature 316:273–275

    Article  CAS  PubMed  Google Scholar 

  38. Ahmad M, Movileanu L (2023) Multiplexed imaging for probing RAS-RAF interactions in living cells. Biochim Biophys Acta 11–1:1865

    Google Scholar 

  39. Miller-Phillips L, Collisson EA (2023) RAS and other molecular targets in pancreatic cancer: the next wave is coming. Curr Treat Options Oncol 24:1–14

    Article  Google Scholar 

  40. Simanshu DK, Nissley DV, McCormick F (2017) RAS proteins and their regulators in human disease. Cell 170:17–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang Y, Ji D, Lei C, Chen Y, Qiu Y, Li X, Li M, Ni D, Pu J, Zhang J, Fu Q, Liu Y, Lu S (2021) Mechanistic insights into the effect of phosphorylation on Ras conformational dynamics and its interactions with cell signaling proteins. Comput Struct Biotechnol J 19:1184–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang Y, Li G, Zhao Y (2023) Advances in the development of Rho GTPase inhibitors. Bioorg Med Chem 90:1–16

    Article  Google Scholar 

  43. Wang H, Liu D, Yu Y, Fang M, Gu X, Long D (2023) Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities. Phys Chem Chem Phys 25:1045–1053

    Article  PubMed  Google Scholar 

  44. Karimi N, Moghaddam SJ (2023) KRAS-Mutant lung cancer: Targeting molecular and immunologic pathways, therapeutic advantages and restrictions. Cells 12:1–26

    Article  Google Scholar 

  45. Lam KK, Wong SH, Cheah PY (2023) Targeting the ‘undruggable’ driver protein KRAS, in epithelial cancers:current prespective. Cells 12:1–16

    Article  Google Scholar 

  46. Grenda A, Krawczyk P, Targowska-Duda KM, Kieszko R, Paśnik I, Milanowski J (2023) Efficacy of dabrafenib and trametinib in a patient with squamous-cell carcinoma, with mutation p.D594G in BRAF and p.R461* in NF1 genes—a case report with literature review. Int J Mol Sci 24:1–11

    Article  Google Scholar 

  47. Cox AD, Der CJ (2010) Ras history. Small GTPases 1:2–27

    Article  PubMed  PubMed Central  Google Scholar 

  48. Iversen L, Tu HL, Lin WC, Christensen SM, Abel SM, Iwig J, Wu HJ, Gureasko J, Rhodes C, Petit RS, Hansen SD, Thill P, Yu CH, Stamou D, Chakraborty AK, Kuriyan J, Groves JT (2014) Molecular kinetics: Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science 345:50–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Duffy MJ, Crown J (2021) Drugging “undruggable” genes for cancer treatment: are we making progress? Int J Cancer 148:8–17

    Article  CAS  PubMed  Google Scholar 

  50. Serna-Blasco R, Sanz-Álvarez M, Aguilera Ó, García-Foncillas J (2019) Targeting the RAS-dependent chemoresistance: the Warburg connection. Semin Cancer Biol 54:80–90

    Article  CAS  PubMed  Google Scholar 

  51. Cercek A, Braghiroli MI, Chou JF, Hechtman JF, Kemeny N, Saltz L, Capanu M, Yaeger R (2017) Clinical features and outcomes of patients with colorectal cancers harboring NRAS mutations. Clin Cancer Res 23:4753–4760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Alam M, Hasan GM, Eldin SM, Adnan M, Riaz MB, Islam A, Khan I, Hassan MI (2023) Investigating regulated signaling pathways in therapeutic targeting of non-small cell lung carcinoma. Biomed Pharmacother 161:1–12

    Article  Google Scholar 

  53. Malayil R, Chhichholiya Y, Vasudeva K, Singh HV, Singh T, Singh S, Munshi A (2023) Oncogenic metabolic reprogramming in breast cancer: focus on signaling pathways and mitochondrial genes. Med Oncol 40:174

    Article  CAS  PubMed  Google Scholar 

  54. Gravandi MM, Abdian S, Tahvilian M, Iranpanah A, Moradi SZ, Fakhri S, Echeverría J (2023) Therapeutic targeting of Ras/Raf/MAPK pathway by natural products: a systematic and mechanistic approach for neurodegeneration. Phytomedicine 115:1–23

    Article  Google Scholar 

  55. Ashrafizadeh M, Mohan CD, Rangappa S, Zarrabi A, Hushmandi K, Kumar AP, Sethi G, Rangappa KS (2023) Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response. Med Res Rev 43:1263–1321

    Article  CAS  PubMed  Google Scholar 

  56. Kiel C, Matallanas D, Kolch W (2021) The ins and outs of RAS effector complexes. Biomolecules 11:1–28

    Article  Google Scholar 

  57. Liu Y, Shen S, Yan Z, Yan L, Ding H, Wang A, Xu Q, Sun L, Yuan Y (2023) Expression characteristics and their functional role of IGFBP gene family in pan-cancer. BMC Cancer 23:1–31

    CAS  Google Scholar 

  58. Lima T, Perpétuo L, Henrique R, Fardilha M, Leite-Moreira A, Bastos J, Vitorino R (2023) Galectin-3 in prostate cancer and heart diseases: a biomarker for these two frightening pathologies? Mol Biol Rep 50:2763–2778

    Article  CAS  PubMed  Google Scholar 

  59. Huang L, Guo Z, Wang F, Fu L (2021) KRAS mutation: from undruggable to druggable in cancer. Sign Transd Target Therap 6:1–20

    Google Scholar 

  60. Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y (2016) Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316–329

    Article  CAS  PubMed  Google Scholar 

  61. Steffen CL, Kaya P, Schaffner-Reckinger E, Abankwa D (2023) Eliminating oncogenic RAS: back to the future at the drawing board. Biochem Soc Trans 51:447–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hondo N, Kitazawa M, Koyama M, Nakamura S, Tokumaru S, Miyazaki S, Kataoka M, Seharada K, Soejima Y (2023) MEK inhibitor and anti-EGFR antibody overcome sotorasib resistance signals and enhance its antitumor effect in colorectal cancer cells. Cancer Lett 567:1–9

    Article  Google Scholar 

  63. Jonckheere N, Vasseur R, Van Seuningen I (2017) The cornerstone K-RAS mutation in pancreatic adenocarcinoma: from cell signaling network, target genes, biological processes to therapeutic targeting. Crit Rev Oncol Hematol 111:7–19

    Article  PubMed  Google Scholar 

  64. Moore AR, Rosenberg SC, McCormick F, Malek S (2020) RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discovery 19:533–552

    Article  CAS  PubMed  Google Scholar 

  65. Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (2005) An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307:1746

    Article  CAS  PubMed  Google Scholar 

  66. Hsu C-H, Weng PW, Chen M-Y, Yeh C-T, Setiawan SA, Yadav VK, Wu ATH, Tzeng DTW, Gong J-X, Yang Z, Tzeng Y-M (2023) Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways. Chem Biol Interact 370:1–12

    Article  Google Scholar 

  67. Baranyi M, Buday L, Hegedűs B (2020) K-Ras prenylation as a potential anticancer target. Cancer Metastasis Rev 39:1127–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alvarado Y, Giles FJ (2007) Ras as a therapeutic target in hematologic malignancies. Expert Opin Emerg Drugs 12:271–284

    Article  CAS  PubMed  Google Scholar 

  69. Marciano D, Ben-Baruch G, Marom M, Egozi Y, Haklai R, Kloog Y (1995) Farnesyl derivatives of rigid carboxylic acids—inhibitors of Ras-dependent cell growth. J Med Chem 38:1267–1272

    Article  CAS  PubMed  Google Scholar 

  70. Yang L, Liu W, Mei H, Zhang Y, Yu X, Xu Y, Li H, Huang J, Zhao Z (2015) Synthesis and biological evaluation of pentanedioic acid derivatives as farnesyltransferase inhibitors. Med Chem Commun 6:671–676

    Article  CAS  Google Scholar 

  71. Schlitzer M, Böhm M, Sattler I (2000) Non-peptidic, non-prenylic bisubstrate farnesyltransferase inhibitors Part 3: structural requirements of the central moiety for farnesyltransferase inhibitory activity. Bioorg Med Chem 8:2399–2406

    Article  CAS  PubMed  Google Scholar 

  72. Haidar M, Jacquemin P (2021) Past and future strategies to inhibit membrane localization of the KRAS oncogene. Int J Mol Sci 22:1–14

    Article  Google Scholar 

  73. Kargbo RB (2019) Treatment of cancers by inhibition of isoprenylcysteine carboxyl methyltransferase. ACS Med Chem Lett 10:1024–1025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Teh JT, Zhu WL, Ilkayeva OR, Li Y, Gooding J, Casey PJ, Summers SA, Newgard CB, Wang M (2015) Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism. Oncogene 34:3296–3304

    Article  CAS  PubMed  Google Scholar 

  75. Lau HY, Wang M (2020) Small change, big effect: taking RAS by the tail through suppression of post-prenylation carboxylmethylation. Small GTPases 11:271–279

    Article  PubMed  Google Scholar 

  76. Winter-Vann AM, Baron RA, Wong W, dela Cruz J, York JD, Gooden DM, Bergo MO, Young SG, Toone EJ, Casey PJ (2005) A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc Natl Acad Sci 102:4336–4341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yang WS, Yeo S-G, Yang S, Kim K-H, Yoo BC, Cho JY (2017) Isoprenyl carboxyl methyltransferase inhibitors: a brief review including recent patents. Amino Acids 49:1469–1485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tamanoi F, Lu J (2013) Recent progress in developing small molecule inhibitors designed to interfere with Ras membrane association: toward inhibiting K-Ras and N-Ras functions. Enzymes 34:181–200

    Article  CAS  PubMed  Google Scholar 

  79. Buchanan MS, Carroll AR, Fechner GA, Boyle A, Simpson MM, Addepalli R, Avery VM, Hooper JNA, Su N, Chen H, Quinn RJ (2007) Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyltransferase, a new cancer target. Bioorg Med Chem Lett 17:6860–6863

    Article  CAS  PubMed  Google Scholar 

  80. Bhadoriya KS, Sharma MC, Jain SV (2015) Pharmacophore modeling and atom-based 3D-QSAR studies on amino derivatives of indole as potent isoprenylcysteine carboxyl methyltransferase (Icmt) inhibitors. J Mol Struct 1081:466–476

    Article  CAS  Google Scholar 

  81. Shih S-P, Lu M-C, El-Shazly M, Lin Y-H, Chen C-L, Yu SS-F, Liu Y-C (2022) The antileukemic and anti-prostatic effect of aeroplysinin-1 is mediated through ROS-induced apoptosis via NOX activation and inhibition of HIF-1a activity. Life 12:1–24

    Article  Google Scholar 

  82. Buchanan MS, Carroll AR, Fechner GA, Boyle A, Simpson M, Addepalli R, Avery VM, Hooper JNA, Cheung T, Chen H, Quinn RJ (2008) Aplysamine 6, an alkaloidal inhibitor of isoprenylcysteine carboxyl methyltransferase from the sponge pseudoceratina sp. J Nat Prod 71:1066–1067

    Article  CAS  PubMed  Google Scholar 

  83. Go M-L, Leow JL, Gorla SK, Schüller AP, Wang M, Casey PJ (2010) Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. J Med Chem 53:6838–6850

    Article  CAS  PubMed  Google Scholar 

  84. Das NR, Sharma T, Goyal N, Singh N, Toropov AA, Toropova AP, Achary PGR (2023) Isoprenylcysteine carboxyl methyltransferase inhibitors: QSAR, docking and molecular dynamics studies. J Mol Struct 1291:1–16

    Article  Google Scholar 

  85. Bergman JA, Hahne K, Song J, Hrycyna CA, Gibbs RA (2012) S-Farnesyl-thiopropionic acid triazoles as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. ACS Med Chem Lett 3:15–19

    Article  CAS  PubMed  Google Scholar 

  86. Ramanujulu PM, Yang T, Yap S-Q, Wong F-C, Casey PJ, Wang M, Go M-L (2013) Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). Eur J Med Chem 63:378–386

    Article  CAS  PubMed  Google Scholar 

  87. Marín-Ramos NI, Balabasquer M, Ortega-Nogales FJ, Torrecillas IR, Gil-Ordóñez A, Marcos-Ramiro B, Aguilar-Garrido P, Cushman I, Romero A, Medrano FJ, Gajate C, Mollinedo F, Philips MR, Campillo M, Gallardo M, Martín-Fontecha M, López-Rodríguez ML, Ortega-Gutiérrez S (2019) A potent isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor improves survival in Ras-driven acute myeloid leukemia. J Med Chem 62:6035–6046

    Article  PubMed  Google Scholar 

  88. Lau HY, Ramanujulu PM, Guo D, Yang T, Wirawan M, Casey PJ, Go M-L, Wang M (2014) An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther 15:1280–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chai TF, Manu KA, Casey PJ, Wang M (2020) Isoprenylcysteine carboxylmethyltransferase is required for the impact of mutant KRAS on TAZ protein level and cancer cell self-renewal. Oncogene 39:5373–5389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Majmudar JD, Hahne K, Hrycyna CA, Gibbs RA (2011) Probing the isoprenylcysteine carboxyl methyltransferase (ICMT) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as ICMT inhibitors. Bioorg Med Chem Lett 21:2616–2620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Marín-Ramos NI, Ortega-Gutiérrez S, López-Rodríguez ML (2019) Blocking Ras inhibition as an antitumor strategy. Semin Cancer Biol 54:91–100

    Article  PubMed  Google Scholar 

  92. Judd WR, Slattum PM, Hoang KC, Bhoite L, Valppu L, Alberts G, Brown B, Roth B, Ostanin K, Huang L, Wettstein D, Richards B, Willardsen JA (2011) Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). J Med Chem 54:5031–5047

    Article  CAS  PubMed  Google Scholar 

  93. Chen X, Yao H, Kashif M, Revêchon G, Eriksson M, Hu J, Wang T, Liu Y, Tüksammel E, Strömblad S, Ahearn IM, Philips MR, Wiel C, Ibrahim MX, Bergo MO (2021) A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells. Elife 10:1–10

    Google Scholar 

  94. Mohammed I, Hampton SE, Ashall L, Hildebrandt ER, Kutlik RA, Manandhar SP, Floyd BJ, Smith HE, Dozier JK, Distefano MD, Schmidt WK, Dore TM (2016) 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorg Med Chem 24:160–178

    Article  CAS  PubMed  Google Scholar 

  95. Knez D, Sosič I, Mitrović A, Pišlar A, Kos J, Gobec S (2020) 8-Hydroxyquinoline-based anti-Alzheimer multimodal agents. Monatshefte für Chemie—Chem Month 151:1111–1120

    Article  CAS  Google Scholar 

  96. Collins M, Pasca Di Magliano M (2014) Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol 4:1–8

    Article  Google Scholar 

  97. Kim S, Kim N, Kang K, Kim W, Won J, Cho J (2019) Whole transcriptome analysis identifies TNS4 as a key effector of cetuximab and a regulator of the oncogenic activity of KRAS mutant colorectal cancer cell lines. Cells 8:1–13

    Article  Google Scholar 

  98. Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PIH, Waldmann H (2013) Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling. Nature 497:638–642

    Article  CAS  PubMed  Google Scholar 

  99. Leung EL-H, Luo LX, Li Y, Liu Z-Q, Li LL, Shi DF, Xie Y, Huang M, Lu LL, Duan FG, Huang JM, Fan XX, Yuan ZW, Ding J, Yao XJ, Ward DC, Liu L (2019) Identification of a new inhibitor of KRAS-PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer. Int J Cancer 145:1334–1345

    Article  CAS  PubMed  Google Scholar 

  100. Liu P, Wang Y, Li X (2019) Targeting the untargetable KRAS in cancer therapy. Acta Pharmaceutica Sinica B 9:871–879

    Article  PubMed  PubMed Central  Google Scholar 

  101. Sun S, Fu J (2018) Methyl-containing pharmaceuticals: methylation in drug design. Bioorg Med Chem Lett 28:3283–3289

    Article  CAS  PubMed  Google Scholar 

  102. Papke B, Murarka S, Vogel HA, Martín-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al-Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PIH (2016) Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat Commun 7:1–9

    Article  Google Scholar 

  103. Murarka S, Martín-Gago P, Schultz-Fademrecht C, Al-Saabi A, Baumann M, Fansa EK, Ismail S, Nussbaumer P, Wittinghofer A, Waldmann H (2017) Development of pyridazinone chemotypes targeting the PDEδ prenyl binding site. Chem Eur J 23:6083–6093

    Article  CAS  PubMed  Google Scholar 

  104. Jiang Y, Zhuang C, Chen L, Lu J, Dong G, Miao Z, Zhang W, Li J, Sheng C (2017) Structural biology-inspired discovery of novel KRAS–PDEδ inhibitors. J Med Chem 60:9400–9406

    Article  CAS  PubMed  Google Scholar 

  105. Chen L, Zhuang C, Lu J, Jiang Y, Sheng C (2018) Discovery of novel KRAS-PDEδ inhibitors by fragment-based drug design. J Med Chem 61:2604–2610

    Article  CAS  PubMed  Google Scholar 

  106. Ismail-Ali A, Fansa EK, Pryk N, Yahiaoui S, Kushnir S, Pflieger M, Wittinghofer A, Schulz F (2016) Biosynthesis-driven structure–activity relationship study of premonensin-derivatives. Org Biomol Chem 14:7671–7675

    Article  CAS  PubMed  Google Scholar 

  107. Kim E, Moore BS, Yoon YJ (2015) Reinvigorating natural product combinatorial biosynthesis with synthetic biology. Nat Chem Biol 11:649–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hanzal-Bayer M, Renault L, Roversi P, Wittinghofer A, Hillig RC (2002) The complex of Arl2-GTP and PDE delta: from structure to function. EMBO J 21:2095–2106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Martín-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schürmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M (2017) A PDE6δ-KRas inhibitor chemotype with up to seven H-bonds and picomolar affinity that prevents efficient inhibitor release by Arl2. Angew Chem 129:2463–2468

    Article  Google Scholar 

  110. Khan I, Rhett JM, O’Bryan JP (1867) Therapeutic targeting of RAS: new hope for drugging the “undruggable.” Biochim Biophys Acta 2020:1–16

    Google Scholar 

  111. Cheng J, Li Y, Wang X, Dong G, Sheng C (2020) Discovery of novel PDEδ degraders for the treatment of KRAS mutant colorectal cancer. J Med Chem 63:7892–7905

    Article  CAS  PubMed  Google Scholar 

  112. Chen L, Zhang J, Wang X, Li Y, Zhou L, Lu X, Dong G, Sheng C (2022) Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models. Acta Pharmaceutica Sinica B 12:274–290

    Article  CAS  PubMed  Google Scholar 

  113. Guo M, He S, Cheng J, Li Y, Dong G, Sheng C (2022) Hydrophobic tagging-induced degradation of PDEδ in colon cancer cells. ACS Med Chem Lett 13:298–303

    Article  PubMed  PubMed Central  Google Scholar 

  114. Nagasaka M, Li Y, Sukari A, Ou S-HI, Al-Hallak MN, Azmi AS (2020) KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev 84:1–8

    Article  Google Scholar 

  115. Siddiqui FA, Alam C, Rosenqvist P, Ora M, Sabt A, Manoharan GB, Bindu L, Okutachi S, Catillon M, Taylor T, Abdelhafez OM, Lönnberg H, Stephen AG, Papageorgiou AC, Virta P, Abankwa D (2020) PDE6D inhibitors with a new design principle selectively block K-Ras activity. ACS Omega 5:832–842

    Article  CAS  PubMed  Google Scholar 

  116. Manoharan GB, Laurini C, Bottone S, BenFredj N, Abankwa DK (2023) K-Ras binds calmodulin-related centrin1 with potential implications for K-Ras driven cancer cell stemness. Cancers 15:1–19

    Article  Google Scholar 

  117. Welsch ME, Kaplan A, Chambers JM, Stokes ME, Bos PH, Zask A, Zhang Y, Sanchez-Martin M, Badgley MA, Huang CS, Tran TH, Akkiraju H, Brown LM, Nandakumar R, Cremers S, Yang WS, Tong L, Olive KP, Ferrando A, Stockwell BR (2017) Multivalent small-molecule pan-RAS inhibitors. Cell 168:878–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tisi R, Spinelli M, Palmioli A, Airoldi C, Cazzaniga P, Besozzi D, Nobile MS, Mazzoleni E, Arnhold S, De Gioia L, Grandori R, Peri F, Vanoni M, Sacco E (2021) The multi-level mechanism of action of a pan-Ras inhibitor explains its antiproliferative activity on cetuximab-resistant cancer cells. Front Mol Biosci 8:1–15

    Article  Google Scholar 

  119. Tanaka T, Thomas J, Van Montfort R, Miller A, Rabbitts T (2021) Pan RAS-binding compounds selected from a chemical library by inhibiting interaction between RAS and a reduced affinity intracellular antibody. Sci Rep 11:1–10

    Google Scholar 

  120. Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Bröker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P (2023) Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619:160–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lu S, Jang H, Zhang J, Nussinov R (2016) Inhibitors of Ras–SOS interactions. ChemMedChem 11:814–821

    Article  CAS  PubMed  Google Scholar 

  122. Hamilton G, Stickler S, Rath B (2023) Targeting of SOS1: from SOS1 activators to proteolysis targeting chimeras. Curr Pharm Des 29:1741–1746

    Article  CAS  PubMed  Google Scholar 

  123. Luo G, Wang B, Hou Q, Wu X (2023) Development of son of sevenless homologue 1 (SOS1) modulators to treat cancers by regulating RAS signaling. J Med Chem 66:4324–4341

    Article  CAS  PubMed  Google Scholar 

  124. Li A, Li X, Zou J, Zhuo X, Chen S, Chai X, Gai C, Xu W, Zhao Q, Zou Y (2023) SOS1-inspired hydrocarbon-stapled peptide as a pan-Ras inhibitor. Bioorg Chem 135:1–10

    Article  Google Scholar 

  125. Jiang H, Fan Y, Wang X, Wang J, Yang H, Fan W, Tang C (2023) Design, synthesis and biological evaluation of quinazoline SOS1 inhibitors. Bioorg Med Chem Lett 88:1–7

    Article  Google Scholar 

  126. Burns C, Sun Q, Daniels RN, Camper D, Kennedy JP, Phan J, Olejniczak ET, Lee T, Waterson AG, Rossanese OW, Fesik SW (2014) Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci 111:3401–3406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yang X, Zhou D, Fu C, Le J, Wang Q, Zhou X, Liu Y, Yuan K, Ding Q (2023) Xiao, Targeting RAS mutants in malignancies: successes, failures, and reasons for hope. Cancer Commun 43:42–74

    Article  CAS  Google Scholar 

  128. Winter JJG, Anderson M, Blades K, Brassington C, Breeze AL, Chresta C, Embrey K, Fairley G, Faulder P, Finlay MRV, Kettle JG, Nowak T, Overman R, Patel SJ, Perkins P, Spadola L, Tart J, Tucker JA, Wrigley G (2015) Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J Med Chem 58:2265–2274

    Article  CAS  PubMed  Google Scholar 

  129. Burns MC, Howes JE, Sun Q, Little AJ, Camper DV, Abbott JR, Phan J, Lee T, Waterson AG, Rossanese OW, Fesik SW (2018) High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling. Anal Biochem 548:44–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Evelyn CR, Duan X, Biesiada J, Seibel WL, Meller J, Zheng Y (2014) Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. Chem Biol 21:1618–1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22

    Article  CAS  PubMed  Google Scholar 

  132. Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Böhnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B (2019) Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proc Natl Acad Sci 116:2551–2560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jin H, Koh M, Lim H, Yong H-Y, Kim E-S, Kim SY, Kim K, Jung J, Ryu W-J, Choi K-Y, Moon A (2023) Lipid raft protein flotillin-1 is important for the interaction between SOS1 and H-Ras/K-Ras, leading to Ras activation. Int J Cancer 152:1933–1946

    Article  CAS  PubMed  Google Scholar 

  134. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H, Rumpel K, Botesteanu D-A, Ettmayer P, Gerstberger T, Kofink C, Wunberg T, Zoephel A, Fu S-C, Teh JL, Böttcher J, Pototschnig N, Schachinger F, Schipany K, Lieb S, Vellano CP, O’Connell JC, Mendes RL, Moll J, Petronczki M, Heffernan TP, Pearson M, McConnell DB, Kraut N (2021) BI-3406, a potent and selective SOS1–KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition, Cancer. Discovery 11:142–157

    CAS  Google Scholar 

  135. He H, Zhang Y, Xu J, Li Y, Fang H, Liu Y, Zhang S (2022) Discovery of orally bioavailable SOS1 inhibitors for suppressing KRAS-driven carcinoma. J Med Chem 65:13158–13171

    Article  CAS  PubMed  Google Scholar 

  136. Sautier B, Nising CF, Wortmann L (2016) Latest advances towards Ras inhibition: a medicinal chemistry perspective. Angew Chem Int Ed 55:15982–15988

    Article  CAS  Google Scholar 

  137. Wilson CY, Tolias P (2016) Recent advances in cancer drug discovery targeting RAS. Drug Discovery Today 21:1915–1919

    Article  CAS  PubMed  Google Scholar 

  138. Avruch J, Xavier R, Bardeesy N, Zhang X-F, Praskova M, Zhou D, Xia F (2009) Rassf family of tumor suppressor polypeptides. J Biol Chem 284:11001–11005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Temraz S, Mukherji D, Shamseddine A (2015) Dual inhibition of MEK and PI3K pathway in KRAS and BRAF mutated colorectal cancers. Int J Mol Sci 16:22976–22988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hoeflich KP, Merchant M, Orr C, Chan J, Den Otter D, Berry L, Kasman I, Koeppen H, Rice K, Yang N-Y, Engst S, Johnston S, Friedman LS, Belvin M (2012) Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Can Res 72:210–219

    Article  CAS  Google Scholar 

  141. Saliani M, Jalal R, Ahmadian MR (2019) From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers. Cancer Biol Med 16:1–27

    Article  Google Scholar 

  142. Jin X-Y, Chen H, Li D-D, Li AL, Wang W-Y, Gu W (2019) Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors. J Enzyme Inhib Med Chem 34:955–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Eleveld TF, Vernooij L, Schild L, Koopmans B, Alles LK, Ebus ME, Dandis R, van Tinteren H, Caron HN, Koster J (2023) MEK inhibition causes BIM stabilization and increased sensitivity to BCL-2 family member inhibitors in RAS-MAPK-mutated neuroblastoma. Front Oncol 13:1–10

    Article  Google Scholar 

  144. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A, Carr D, Deng Y, Jin W, Black S, Long B, Liu J, DiNunzio E, Windsor W, Zhang R, Zhao S, Angagaw MH, Pinheiro EM, Desai J, Xiao L, Shipps G, Hruza A, Wang J, Kelly J, Paliwal S, Gao X, Babu BS, Zhu L, Daublain P, Zhang L, Lutterbach BA, Pelletier MR, Philippar U, Siliphaivanh P, Witter D, Kirschmeier P, Bishop WR, Hicklin D, Gilliland DG, Jayaraman L, Zawel L, Fawell S, Samatar AA (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750

    Article  CAS  PubMed  Google Scholar 

  145. Komatsu M, Nakamura K, Takeda T, Chiwaki F, Banno K, Aoki D, Takeshita F, Sasaki H (2022) Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling. Oncogene 41:2326–2339

    Article  CAS  PubMed  Google Scholar 

  146. Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K-I, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T (2013) In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras–effector interaction. Proc Natl Acad Sci 110:8182–8187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Shima F, Yoshikawa Y, Matsumoto S, Kataoka T (2013) Discovery of small-molecule Ras inhibitors that display antitumor activity by interfering with Ras GTP–effector interaction. Enzymes 34:1–23

    Article  CAS  PubMed  Google Scholar 

  148. Marín-Ramos NI, Piñar C, Vázquez-Villa H, Martín-Fontecha M, González Á, Canales Á, Algar S, Mayo PP, Jiménez-Barbero J, Gajate C (2017) Development of a nucleotide exchange inhibitor that impairs Ras oncogenic signaling. Chem—Eur J 23:1676–1685

    Article  PubMed  Google Scholar 

  149. Xie C, Li Y, Li L-L, Fan X-X, Wang Y-W, Wei C-L, Liu L, Leung EL-H, Yao X-J (2017) Identification of a new potent inhibitor targeting KRAS in non-small cell lung cancer cells. Front Pharmacol 8:1–8

    Article  Google Scholar 

  150. Bannoura SF, Uddin MH, Nagasaka M, Fazili F, Al-Hallak MN, Philip PA, El-Rayes B, Azmi AS (2021) Targeting KRAS in pancreatic cancer: new drugs on the horizon. Cancer Metastasis Rev 40:1–17

    Article  Google Scholar 

  151. Lai H, Wang Y, Duan F, Li Y, Jiang Z, Luo L, Liu L, Leung ELH, Yao X (2018) Krukovine suppresses KRAS-mutated lung cancer cell growth and proliferation by inhibiting the RAF-ERK pathway and inactivating AKT pathway. Front Pharmacol 9:1–9

    Article  Google Scholar 

  152. Lee J-H, Lee S-H, Lee S-K, Choi J-H, Lim S, Kim M-S, Lee K-M, Lee M-W, Ku J-L, Kim D-H (2023) Antiproliferative activity of krukovine by regulating transmembrane protein 139 (TMEM139) in oxaliplatin-resistant pancreatic cancer cells. Cancers 15:1–17

    Google Scholar 

  153. Zhang Y, Meng X, Tang H, Cheng M, Yang F, Xu W (2020) Design, synthesis, and biological evaluation of novel substituted thiourea derivatives as potential anticancer agents for NSCLC by blocking K-Ras protein-effectors interactions. J Enzyme Inhib Med Chem 35:344–353

    Article  CAS  PubMed  Google Scholar 

  154. Zhao Z, Bohidar N, Bourne PE (2023) Analysis of KRAS–ligand interaction modes and flexibilities reveals the binding characteristics. J Chem Inf Model 63:1362–1370

    Article  CAS  PubMed  Google Scholar 

  155. Tanaka T, Williams RL, Rabbitts TH (2007) Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS. EMBO J 26:3250–3259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Cabot D (2020) Analysis of KRAS phosphorylation and KRAS effector domain as targets for cancer therapy. In: University of Barcelona, pp. 1–280.

  157. Quevedo CE, Cruz-Migoni A, Bery N, Miller A, Tanaka T, Petch D, Bataille CJR, Lee LYW, Fallon PS, Tulmin H, Ehebauer MT, Fernandez-Fuentes N, Russell AJ, Carr SB, Phillips SEV, Rabbitts TH (2018) Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun 9:1–12

    Article  CAS  Google Scholar 

  158. Upadhyaya P, Bedewy W, Pei D (2016) Direct inhibitors of Ras-effector protein interactions. Mini Rev Med Chem 16:376–382

    Article  CAS  PubMed  Google Scholar 

  159. Cruz-Migoni A, Canning P, Quevedo CE, Bataille CJR, Bery N, Miller A, Russell AJ, Phillips SEV, Carr SB, Rabbitts TH (2019) Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc Natl Acad Sci 116:2545–2550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Mattox TE, Chen X, Maxuitenko YY, Keeton AB, Piazza GA (2019) Exploiting RAS nucleotide cycling as a strategy for drugging RAS-driven cancers. Int J Mol Sci 21:1–14

    Article  Google Scholar 

  161. Ni D, Li X, He X, Zhang H, Zhang J, Lu S (2019) Drugging K-RasG12C through covalent inhibitors: mission possible? Pharmacol Ther 202:1–17

    Article  CAS  PubMed  Google Scholar 

  162. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ostrem JM, Shokat KM (2016) Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov 15:771–785

    Article  CAS  PubMed  Google Scholar 

  164. Zeng M, Lu J, Li L, Feru F, Quan C, Gero TW, Ficarro SB, Xiong Y, Ambrogio C, Paranal RM, Catalano M, Shao J, Wong K-K, Marto JA, Fischer ES, Jänne PA, Scott DA, Westover KD, Gray NS (2017) Potent and selective covalent quinazoline inhibitors of KRAS G12C. Cell Chem Biol 24:1005–1016

    Article  CAS  PubMed  Google Scholar 

  165. Li L, Zhao H, Peng X, Liu J, Mai R, Chen J, Lin L, Chen T, Yan J, Shi J, Chen J (2022) Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents. Bioorg Med Chem 71:1–10

    Article  Google Scholar 

  166. Janes MR, Zhang J, Li L-S, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ, Darjania L, Feng J, Chen JH, Li S, Li S, Long YO, Thach C, Liu Y, Zarieh A, Ely T, Kucharski JM, Kessler LV, Wu T, Yu K, Wang Y, Yao Y, Deng X, Zarrinkar PP, Brehmer D, Dhanak D, Lorenzi MV, Hu-Lowe D, Patricelli MP, Ren P, Liu Y (2018) Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172:578–589

    Article  CAS  PubMed  Google Scholar 

  167. Fell JB, Fischer JP, Baer BR, Ballard J, Blake JF, Bouhana K, Brandhuber BJ, Briere DM, Burgess LE, Burkard MR (2018) Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med Chem Lett 9:1230–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen H, Smaill JB, Liu T, Ding K, Lu X (2020) Small-molecule inhibitors directly targeting KRAS as anticancer therapeutics. J Med Chem 63:14404–14424

    Article  CAS  PubMed  Google Scholar 

  169. Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM et al (2020) Identifcation of the clinical development candidate MRTX849, a covalent KRAS(G12C) inhibitor for the treatment of cancer. J Med Chem 63(13):6679–6693

    Article  CAS  PubMed  Google Scholar 

  170. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang H-L, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, SanMiguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, Cee VJ (2020) Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem 63:52–65

    Article  CAS  PubMed  Google Scholar 

  171. Pantsar T (2020) KRAS (G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations. Sci Rep 10:1–9

    Article  Google Scholar 

  172. Zhang X, Zhao T, Sun M, Li P, Lai M, Xie L, Chen J, Ding J, Xie H, Zhou J, Zhang H (2023) Design, synthesis and biological evaluation of KRASG12C-PROTACs. Bioorg Med Chem 78:1–14

    Article  Google Scholar 

  173. Liu M, Zhou G, Su W, Gu Y, Gao M, Wang K, Huo R, Li Y, Zhou Z, Chen K, Zheng M, Zhang S, Xu T (2023) Design, synthesis, and bioevaluation of pyrido[2,3-d]pyrimidin-7-ones as potent SOS1 inhibitors. ACS Med Chem Lett 14:183–190

    Article  CAS  PubMed  Google Scholar 

  174. Morstein J et al (2023) Direct modulators of K-Ras–membrane interactions. ACS Chem Biol 18(9):2082–2093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Wang X et al (2021) Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor. J Med Chem 65(4):3123–3133

    Article  PubMed  Google Scholar 

  176. Yu Z et al (2023) Simultaneous covalent modification of K-Ras (G12D) and K-Ras (G12C) with tunable oxirane electrophiles. J Am Chem Soc 145:20403–20411

    Article  CAS  PubMed  Google Scholar 

  177. Gbelcová H, Rimpelová S, Knejzlík Z, Šáchová J, Koláˇr M, Strnad H, Repiská V, D’Acunto WC, Ruml T, Vítek L (2017) Isoprenoids responsible for protein prenylation modulate the biological effects of statins on pancreatic cancer cells. Lipids Health Dis 16:1–10

    Article  Google Scholar 

  178. Datta A, Kim H, Lal M, McGee L, Johnson A, Moustafa AA, Jones JC, Mondal D, Ferrer M, Abdel-Mageed AB (2017) Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells. Cancer Lett 408:73–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kumar S, Agnihotri N (2019) Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer. Biomed Pharmacother 109:1462–1477

    Article  CAS  PubMed  Google Scholar 

  180. Ho CL, Wang JL, Lee CC, Cheng HY, Wen WC, Cheng HH, Chen MC (2014) Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells. Biomed Pharmacother 68:1007–1014

    Article  CAS  PubMed  Google Scholar 

  181. Kumar VB, Yuan TC, Liou JW, Yang CJ, Sung PJ, Weng CF (2011) Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles. Mutat Res 707:42–52

    Article  CAS  PubMed  Google Scholar 

  182. Ganaie AA, Siddique HR, Sheikh IA, Parray A, Wang L, Panyam J, Villalta PW, Deng Y, Konety BR, Saleem M (2020) A novel terpenoid class for prevention and treatment of KRAS-driven cancers: comprehensive analysis using in situ, in vitro, and in vivo model systems. Mol Carcinog 59:886–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hirata Y, Shigemura K, Moriwaki M, Iwatsuki M, Kan Y, Ooya T, Maeda K, Yang Y, Nakashima T, Matsuo H, Nakanishi J (2023) Growth and migration blocking effect of nanaomycin K, a compound produced by streptomyces sp., on prostate cancer cell lines in vitro and in vivo. Cancers 15(10):2684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Najumudeen AK, Jaiswal A, Lectez B, Oetken-Lindholm C, Guzmán C, Siljamäki E, Posada IMD, Lacey E, Aittokallio T, Abankwa D (2016) Cancer stem cell drugs target K-ras signaling in a stemness context. Oncogene 35:5248–5262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Prieur A, Cappellini M, Habif G, Lefranc M-P, Mazard T, Morency E, Pascussi J-M, Flacelière M, Cahuzac N, Vire B (2017) Targeting the wnt pathway and cancer stem cells with anti-progastrin humanized antibodies as a potential treatment for K-RAS-mutated colorectal cancer anti-progastrin antibody for K-RAS–mutated colorectal cancer. Clin Cancer Res 23:5267–5280

    Article  CAS  PubMed  Google Scholar 

  186. Cha P-H, Cho Y-H, Lee S-K, Lee J, Jeong W-J, Moon B-S, Yun J-H, Yang JS, Choi S, Yoon J, Kim H-Y, Kim M-Y, Kaduwal S, Lee W, Min DS, Kim H, Han G, Choi K-Y (2016) Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation. Nat Chem Biol 12:593–600

    Article  CAS  PubMed  Google Scholar 

  187. Jeong W-J, Ro EJ, Choi K-Y (2018) Interaction between Wnt/β-catenin and RAS-ERK pathways and an anti-cancer strategy via degradations of β-catenin and RAS by targeting the Wnt/β-catenin pathway. NPJ Precision Oncol 2:1–10

    CAS  Google Scholar 

  188. Cho Y-H, Cha P-H, Kaduwal S, Park J-C, Lee S-K, Yoon J-S, Shin W, Kim H, Ro EJ, Koo K-H (2016) KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer. Oncotarget 7:1–14

    Article  Google Scholar 

  189. Kim Y, Kang M-H, Cho Y-H (2022) API-2-induced cell migration is overcome by small molecular approaches inhibiting β-catenin. Curr Issues Mol Biol 44:6006–6014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Shin W, Lee S-K, Hwang J-H, Park J-C, Cho Y-H, Ro EJ, Song Y, Seo HR, Choi K-Y (2018) Identification of Ras-degrading small molecules that inhibit the transformation of colorectal cancer cells independent of β-catenin signaling. Exp Mol Med 50:1–10

    PubMed  PubMed Central  Google Scholar 

  191. Ro EJ, Cho Y-H, Jeong W-J, Park J-C, Min DS, Choi K-Y (2019) WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. Cell Commun Signal 17:1–13

    Article  CAS  Google Scholar 

  192. Xu K, Park D, Magis AT, Zhang J, Zhou W, Sica GL, Ramalingam SS, Curran WJ, Deng X (2019) Small molecule KRAS agonist for mutant KRAS cancer therapy. Mol Cancer 18:1–16

    Article  Google Scholar 

  193. Ren S, Wang X, Song J, Jin G (2021) Discovery of novel ibrutinib analogues to treat malignant melanoma. Bioorg Chem 117:1–10

    Article  Google Scholar 

  194. Kessler D, Gmachl M, Mantoulidis A, Martin LJ, Zoephel A, Mayer M, Gollner A, Covini D, Fischer S, Gerstberger T (2019) Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci 116:15823–15829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Zheng Q, Peacock DM, Shokat KM (2022) Drugging the next undruggable KRAS allele-Gly12Asp. J Med Chem 65:3119–3122

    Article  CAS  PubMed  Google Scholar 

  196. Tran TH, Alexander P, Dharmaiah S, Agamasu C, Nissley DV, McCormick F, Esposito D, Simanshu DK, Stephen AG, Balius TE (2020) The small molecule BI-2852 induces a nonfunctional dimer of KRAS. Proc Natl Acad Sci 117:3363–3364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Vasta JD, Peacock DM, Zheng Q, Walker JA, Zhang Z, Zimprich CA, Thomas MR, Beck MT, Binkowski BF, Corona CR (2022) KRAS is vulnerable to reversible switch-II pocket engagement in cells. Nat Chem Biol 18:596–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Nan X, Pitt C, McCormick F, Chu S (2013) US national cancer institute’s new Ras project targets an old foe. Nat Med 19:1–2

    Google Scholar 

Download references

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through the Large Group Research Project under grant number (RGP2/321/44).

Funding

This work is supported by the Deanship of Scientific Research at King Khalid University for funding this work through the Large Group Research Project under Grant Number (RGP2/321/44).

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Authors and Affiliations

  1. Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, Egypt

    Ahmed Sabt

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt

    Haytham O. Tawfik

  3. Department of Medical Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia

    Eman F. Khaleel & Rehab Mustafa Badi

  4. Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt

    Hoda Atef Abdelsattar Ibrahim

  5. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, 13713, Riyadh, Saudi Arabia

    Eslam B. Elkaeed

  6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt

    Wagdy M. Eldehna

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  1. Ahmed Sabt
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  2. Haytham O. Tawfik
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  4. Rehab Mustafa Badi
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Contributions

A.S., H.O.T. and W.M.E. made the concept and all authors wrote, editing, and reviewed the manuscript.

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Correspondence to Ahmed Sabt, Haytham O. Tawfik or Wagdy M. Eldehna.

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Sabt, A., Tawfik, H.O., Khaleel, E.F. et al. An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10777-6

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