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Inhibitors of the p21 Activated Kinases

  • Kinase Inhibitor (A Minden, Section Editor)
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Abstract

This review article provides an overview of some of the inhibitors that have been generated against the p21-activated kinases (PAKs). Immunohistopathological evaluation, gene profiling studies, and functional assays have indicated that PAKs play important roles in human diseases, particularly cancer. Many tumor samples that have been evaluated have shown overexpression or amplification of PAK genes. Furthermore, several studies have also shown that PAKs are involved in brain diseases as well as infectious diseases. Since the PAK kinases have been linked to cancer and other diseases, they are often considered to be valuable therapeutic targets. A number of PAK inhibitors are currently under study for their use in research or as therapeutic agents. In some cases, promising results have been obtained from both in vivo and in vitro studies. Studies are ongoing to assess the specificity of PAK inhibitors toward specific PAK isoforms, to determine their pharmacokinetic profiles, and to determine optimal doses. Future studies will determine which PAK inhibitors will be the most promising candidates for clinical development.

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References

  1. Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, et al. Novel p21-activated kinase 4 (PAK4) allosteric modulators overcome drug resistance and Stemness in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2017;16(1):76–87. https://doi.org/10.1158/1535-7163.MCT-16-0205.

    Article  CAS  PubMed  Google Scholar 

  2. Abu Aboud O, Chen CH, Senapedis W, Baloglu E, Argueta C, Weiss RH. Dual and specific inhibition of NAMPT and PAK4 by KPT-9274 decreases kidney Cancer growth. Mol Cancer Ther. 2016;15(9):2119–29. https://doi.org/10.1158/1535-7163.MCT-16-0197.

    Article  CAS  PubMed  Google Scholar 

  3. Aoki H, Yokoyama T, Fujiwara K, Tari AM, Sawaya R, Suki D, et al. Phosphorylated Pak1 level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. Clin Cancer Res. 2007;13(22 Pt 1):6603–9. https://doi.org/10.1158/1078-0432.CCR-07-0145.

    Article  CAS  PubMed  Google Scholar 

  4. Arias-Romero LE, Villamar-Cruz O, Pacheco A, Kosoff R, Huang M, Muthuswamy SK, et al. A Rac-Pak signaling pathway is essential for ErbB2-mediated transformation of human breast epithelial cancer cells. Oncogene. 2010;29(43):5839–49. doi: onc2010318 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Azmi AS, Aboukameel A, Bao B, Sarkar FH, Philip PA, Kauffman M, et al. Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterology. 2013;144(2):447–56. https://doi.org/10.1053/j.gastro.2012.10.036.

    Article  CAS  PubMed  Google Scholar 

  6. Azmi AS, Muqbil I, Wu J, Aboukameel A, Senapedis W, Baloglu E, et al. Targeting the nuclear export protein XPO1/CRM1 reverses epithelial to mesenchymal transition. Sci Rep. 2015;5:16077. https://doi.org/10.1038/srep16077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baek HY, Lim JW, Kim H. Interaction between the Helicobacter pylori CagA and alpha-pix in gastric epithelial AGS cells. Ann N Y Acad Sci. 2007;1096:18–23. https://doi.org/10.1196/annals.1397.065.

    Article  CAS  PubMed  Google Scholar 

  8. Begum A, Imoto I, Kozaki K, Tsuda H, Suzuki E, Amagasa T, et al. Identification of PAK4 as a putative target gene for amplification within 19q13.12-q13.2 in oral squamous-cell carcinoma. Cancer Sci. 2009;100(10):1908–16. https://doi.org/10.1111/j.1349-7006.2009.01252.x.

    Article  CAS  PubMed  Google Scholar 

  9. Cai S, Ye Z, Wang X, Pan Y, Weng Y, Lao S, et al. Overexpression of P21-activated kinase 4 is associated with poor prognosis in non-small cell lung cancer and promotes migration and invasion. J Exp Clin Cancer Res. 2015;34:48. https://doi.org/10.1186/s13046-015-0165-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen S, Auletta T, Dovirak O, Hutter C, Kuntz K, El-Ftesi S, et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol Ther. 2008;7(11):1793–802. doi: 6840 [pii]

    Article  CAS  PubMed  Google Scholar 

  11. Chen SY, Huang PH, Cheng HJ. Disrupted-in-schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci U S A. 2011;108(14):5861–6. https://doi.org/10.1073/pnas.1018128108.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen H, Miao J, Li H, Wang C, Li J, Zhu Y, et al. Expression and prognostic significance of p21-activated kinase 6 in hepatocellular carcinoma. J Surg Res. 2014;189(1):81–8. https://doi.org/10.1016/j.jss.2014.01.049.

    Article  CAS  PubMed  Google Scholar 

  13. Chen J, Lu H, Yan D, Cui F, Wang X, Yu F, et al. PAK6 increase chemoresistance and is a prognostic marker for stage II and III colon cancer patients undergoing 5-FU based chemotherapy. Oncotarget. 2015;6(1):355–67. https://doi.org/10.18632/oncotarget.2803.

    Article  PubMed  Google Scholar 

  14. Crawford JJ, Lee W, Aliagas I, Mathieu S, Hoeflich KP, Zhou W, et al. Structure-guided design of group I selective p21-activated kinase inhibitors. J Med Chem. 2015;58(12):5121–36. https://doi.org/10.1021/acs.jmedchem.5b00572.

    Article  CAS  PubMed  Google Scholar 

  15. Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, et al. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol. 2008;15(4):322–31. https://doi.org/10.1016/j.chembiol.2008.03.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankaranarayana Rao BS, Ko HY, et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc Natl Acad Sci U S A. 2013;110(14):5671–6. https://doi.org/10.1073/pnas.1219383110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fang ZP, Jiang BG, Gu XF, Zhao B, Ge RL, Zhang FB. P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma. Acta Pharmacol Sin. 2014;35(1):82–8. https://doi.org/10.1038/aps.2013.31.

    Article  CAS  PubMed  Google Scholar 

  18. Fulciniti M, Martinez-Lopez J, Senapedis W, Oliva S, Lakshmi Bandi R, Amodio N, et al. Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma. Blood. 2017;129(16):2233–45. https://doi.org/10.1182/blood-2016-06-724831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao C, Ma T, Pang L, Xie R. Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer. Diagn Pathol. 2014;9:55. https://doi.org/10.1186/1746-1596-9-55.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Goc A, Al-Azayzih A, Abdalla M, Al-Husein B, Kuvuri S, Lee J, et al. P21 activated Kinase-1 (Pak1) promotes prostate tumor growth and Microinvasion via inhibition of transforming growth factor β expression and enhanced matrix metalloproteinase 9 secretion. J Biochem. 2013;288:3025–35. https://doi.org/10.1074/jbc.M112.424770.

    Article  CAS  Google Scholar 

  21. Gu J, Li K, Li M, Wu X, Zhang L, Ding Q, et al. A role for p21-activated kinase 7 in the development of gastric cancer. FEBS J. 2013;280(1):46–55. https://doi.org/10.1111/febs.12048.

    Article  CAS  PubMed  Google Scholar 

  22. Gu X, Wang C, Wang X, Ma G, Li Y, Cui L, et al. Efficient inhibition of human glioma development by RNA interference-mediated silencing of PAK5. Int J Biol Sci. 2015;11(2):230–7. https://doi.org/10.7150/ijbs.9193.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guo Q, Su N, Zhang J, Li X, Miao Z, Wang G, et al. PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis. Oncogene. 2014;33(25):3277–87. https://doi.org/10.1038/onc.2013.296.

    Article  CAS  PubMed  Google Scholar 

  24. Han K, Zhou Y, Gan ZH, Qi WX, Zhang JJ, Fen T, et al. p21-activated kinase 7 is an oncogene in human osteosarcoma. Cell Biol Int. 2014;38(12):1394–402. https://doi.org/10.1002/cbin.10351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hao C, Li X, Song S, Guo B, Guo J, Zhang J, et al. Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion. Org Biomol Chem. 2016;14(32):7676–90. https://doi.org/10.1039/c6ob01072e.

    Article  CAS  PubMed  Google Scholar 

  26. Hao C, Zhao F, Song HY, Guo J, Li X, Jiang X, et al. Structure-based design of 6-chloro-4-aminoquinazoline-2-carboxamide derivatives as potent and selective p21-activated kinase 4 (PAK4) inhibitors. J Med Chem. 2017;61(1):265–85. https://doi.org/10.1021/acs.jmedchem.7b01342.

    Article  CAS  PubMed  Google Scholar 

  27. Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, et al. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci U S A. 2007;104(27):11489–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. He LF, Xu HW, Chen M, Xian ZR, Wen XF, Chen MN, et al. Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling. Oncotarget. 2017;8(11):17573–85. https://doi.org/10.18632/oncotarget.7466.

    Article  PubMed  Google Scholar 

  29. Huang K, Chen G, Luo J, Zhang Y, Xu G. Clinicopathological and cellular signature of PAK1 in human bladder cancer. Tumour Biol. 2015;36(4):2359–68. https://doi.org/10.1007/s13277-014-2843-7.

    Article  CAS  PubMed  Google Scholar 

  30. Huynh N, Beutler JA, Shulkes A, Baldwin GS, He H. Glaucarubinone inhibits colorectal cancer growth by suppression of hypoxia-inducible factor 1alpha and beta-catenin via a p-21 activated kinase 1-dependent pathway. Biochim Biophys Acta. 2015;1853(1):157–65. https://doi.org/10.1016/j.bbamcr.2014.10.013.

    Article  CAS  PubMed  Google Scholar 

  31. Hwang VJ, Zhou X, Chen X, Trott J, Abu Aboud O, Shim K, et al. Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease. Kidney Int. 2017;92(4):922–33. https://doi.org/10.1016/j.kint.2017.03.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jagadeeshan S, Venkatraman G, Rayala SK. Targeting p21 activated kinase 1 (Pak1) to PAKup pancreatic cancer. Expert Opin Ther Targets. 2016;20(11):1283–5. https://doi.org/10.1080/14728222.2016.1239719.

    Article  PubMed  Google Scholar 

  33. Kalyaanamoorthy S, Barakat KH. Development of safe drugs: the hERG challenge. Med Res Rev. 2017;38(2):525–55. https://doi.org/10.1002/med.21445.

    Article  PubMed  Google Scholar 

  34. Kamai T, Shirataki H, Nakanishi K, Furuya N, Kambara T, Abe H, et al. Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer. BMC Cancer. 2010;10:164. https://doi.org/10.1186/1471-2407-10-164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Karpov AS, Amiri P, Bellamacina C, Bellance MH, Breitenstein W, Daniel D, et al. Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitor. ACS Med Chem Lett. 2015;6(7):776–81. https://doi.org/10.1021/acsmedchemlett.5b00102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Karthikeyan S, Hoti SL, Nazeer Y, Hegde HV. Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways. Oncotarget. 2016;7(27):42353–73. https://doi.org/10.18632/oncotarget.9865.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kaur R, Yuan X, Lu ML, Balk SP. Increased PAK6 expression in prostate cancer and identification of PAK6 associated proteins. Prostate. 2008;68(14):1510–6. https://doi.org/10.1002/pros.20787.

    Article  CAS  PubMed  Google Scholar 

  38. Kesanakurti D, Chetty C, Rajasekhar Maddirela D, Gujrati M, Rao JS. Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma. Cell Death Dis. 2012;3:e445. https://doi.org/10.1038/cddis.2012.182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim MJ, Biag J, Fass DM, Lewis MC, Zhang Q, Fleishman M, et al. Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1-PAK3 signaling in neuroplasticity. Mol Psychiatry. 2017;22(3):417–29. https://doi.org/10.1038/mp.2016.98.

    Article  CAS  PubMed  Google Scholar 

  40. King H, Nicholas NS, Wells CM. Role of p-21-activated kinases in cancer progression. Int Rev Cell Mol Biol. 2014;309:347–87. https://doi.org/10.1016/B978-0-12-800255-1.00007-7.

    Article  CAS  PubMed  Google Scholar 

  41. Kumar R, Li DQ. PAKs in human cancer progression: From inception to cancer therapeutics to future oncobiology. Adv Canc Res. 2016;130:137–209. https://doi.org/10.1016/bs.acr.2016.01.002.

    Article  CAS  Google Scholar 

  42. Kumar R, Sanawar R, Li X, Li F. Structure, biochemistry, and biology of PAK kinases. Gene. 2017;605:20–31. https://doi.org/10.1016/j.gene.2016.12.014.

    Article  CAS  PubMed  Google Scholar 

  43. Lee W, Crawford JJ, Aliagas I, Murray LJ, Tay S, Wang W, et al. Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors. Bioorg Med Chem Lett. 2016;26(15):3518–24. https://doi.org/10.1016/j.bmcl.2016.06.031.

    Article  CAS  PubMed  Google Scholar 

  44. Li X, Wen W, Liu K, Zhu F, Malakhova M, Peng C, et al. Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines. J Biol Chem. 2011;286(25):22291–9. doi: M111.236596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li D, Yao X, Zhang P. The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer. Mol Cell Biochem. 2013a;383(1–2):191–9. https://doi.org/10.1007/s11010-013-1767-7.

    Article  CAS  PubMed  Google Scholar 

  46. Li Z, Zou X, Xie L, Dong H, Chen Y, Liu Q, et al. Prognostic importance and therapeutic implications of PAK1, a drugable protein kinase, in gastroesophageal junction adenocarcinoma. PLoS One. 2013b;8(11):e80665. https://doi.org/10.1371/journal.pone.0080665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, et al. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013;288(40):29105–14. https://doi.org/10.1074/jbc.M113.510933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu Y, Chen N, Cui X, Zheng X, Deng L, Price S, et al. The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis. Oncogene. 2010a;29(44):5883–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu RX, Wang WQ, Ye L, Bi YF, Fang H, Cui B, et al. p21-activated kinase 3 is overexpressed in thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome and participates in cell migration. Endocrine. 2010b;38(1):38–47. https://doi.org/10.1007/s12020-010-9324-6.

    Article  CAS  PubMed  Google Scholar 

  50. Lu W, Xia YH, Qu JJ, He YY, Li BL, Lu C, et al. p21-activated kinase 4 regulation of endometrial cancer cell migration and invasion involves the ERK1/2 pathway mediated MMP-2 secretion. Neoplasma. 2013;60(5):493–503. https://doi.org/10.4149/neo_2013_064.

    Article  CAS  PubMed  Google Scholar 

  51. Luo S, Mizuta H, Rubinsztein DC. p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity. Hum Mol Genet. 2008;17(6):895–905. https://doi.org/10.1093/hmg/ddm362.

    Article  CAS  PubMed  Google Scholar 

  52. Ma QL, Yang F, Frautschy SA, Cole GM. PAK in Alzheimer disease, Huntington disease and X-linked mental retardation. Cell Logist. 2012;2(2):117–25. https://doi.org/10.4161/cl.21602.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mak GW, Chan MM, Leong VY, Lee JM, Yau TO, Ng IO, et al. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Res. 2011;71(8):2949–58. doi: 0008-5472.CAN-10-4046 [pii]

    Article  CAS  PubMed  Google Scholar 

  54. Maksimoska J, Feng L, Harms K, Yi C, Kissil J, Marmorstein R, et al. Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. J Am Chem Soc. 2008;130(47):15764–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014;28(5):656–72. https://doi.org/10.1002/ptr.5054.

    Article  PubMed  Google Scholar 

  56. McCarty SK, Saji M, Zhang X, Jarjoura D, Fusco A, Vasko VV, et al. Group I p21-activated kinases regulate thyroid cancer cell migration and are overexpressed and activated in thyroid cancer invasion. Endocr Relat Cancer. 2010;17(4):989–99. https://doi.org/10.1677/ERC-10-0168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McCoull W, Hennessy EJ, Blades K, Chuaqui C, Dowling JE, Ferguson AD, et al. Optimization of highly kinase selective Bis-anilino pyrimidine PAK1 inhibitors. ACS Med Chem Lett. 2016;7(12):1118–23. https://doi.org/10.1021/acsmedchemlett.6b00322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mohammad RM, Li Y, Muqbil I, Aboukameel A, Senapedis W, Baloglu E, et al. Targeting rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation. Small GTPases. 2017;0:1–11. https://doi.org/10.1080/21541248.2017.1329694.

    Article  CAS  Google Scholar 

  59. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A. 2010;107(20):9446–51. doi: 0911863107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ndubaku CO, Crawford JJ, Drobnick J, Aliagas I, Campbell D, Dong P, et al. Design of Selective PAK1 inhibitor G-5555: improving properties by employing an unorthodox low-pK a polar moiety. ACS Med Chem Lett. 2015;6(12):1241–6. https://doi.org/10.1021/acsmedchemlett.5b00398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nguyen DG, Wolff KC, Yin H, Caldwell JS, Kuhen KL. "UnPAKing" human immunodeficiency virus (HIV) replication: using small interfering RNA screening to identify novel cofactors and elucidate the role of group I PAKs in HIV infection. J Virol. 2006;80(1):130–7. https://doi.org/10.1128/JVI.80.1.130-137.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nguyen BC, Takahashi H, Uto Y, Shahinozzaman MD, Tawata S, Maruta H. 1,2,3-Triazolyl ester of ketorolac: a "click chemistry"-based highly potent PAK1-blocking cancer-killer. Eur J Med Chem. 2017a;126:270–6.

    Article  CAS  PubMed  Google Scholar 

  63. Nguyen BCQ, Yoshimura K, Kumazawa S, Tawata S, Maruta H. Frondoside a from sea cucumber and nymphaeols from Okinawa propolis: natural anti-cancer agents that selectively inhibit PAK1 in vitro. Drug Discov Ther. 2017b;11(2):110–4.

    Article  CAS  PubMed  Google Scholar 

  64. Ong CC, Jubb AM, Haverty PM, Zhou W, Tran V, Truong T, et al. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2011;108(17):7177–82. https://doi.org/10.1073/pnas.1103350108.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ong CC, Jubb AM, Jakubiak D, Zhou W, Rudolph J, Haverty PM, et al. P21-activated kinase 1 (PAK1) as a therapeutic target in BRAF wild-type melanoma. Journal of National Cancer Institute. 2013;105:606–7. https://doi.org/10.1093/jnci/djt054.

    Article  CAS  Google Scholar 

  66. Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W, et al. Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. Breast Cancer Res. 2015;17:59. https://doi.org/10.1186/s13058-015-0564-5.

  67. Osman AB, Gani SM, Engh A. Protein kinase inhibition of clinically important staurosporine analogues. Nat Prod Rep. 2010;27:489–98.

    Article  Google Scholar 

  68. Pozueta J, Lefort R, Shelanski ML. Synaptic changes in Alzheimer's disease and its models. Neuroscience. 2013;251:51–65. https://doi.org/10.1016/j.neuroscience.2012.05.050.

    Article  CAS  PubMed  Google Scholar 

  69. Pyronneau A, He Q, Hwang JY, Porch M, Contractor A, Zukin RS. Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome. Sci Signal. 2017;10(504):eaan0852. https://doi.org/10.1126/scisignal.aan0852.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rane C, Minden A. P21 activated kinases: structure, regulation, and functions. Semin in Cancer Biol. 2014;5:e28003. https://doi.org/10.4161/sgtp.28003.

    Article  Google Scholar 

  71. Rane C, Senapedis W, Baloglu E, Landesman Y, Crochiere M, Das-Gupta S, et al. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. Sci Rep. 2017;7:42555. https://doi.org/10.1038/srep42555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rosen LS, Blumenkopf TA, Breazna A, Darang S, Gallo JD, Goldman J, Wang D, Mileshkin L, and Eckhardt SG. "Phase 1, dose-escalation, safety, pharmacokinetic and pharmacodynamic study of single agent PF-03758309, an oral PAK inhibitor, in patients with advanced solid tumors." New Mol Ther. 2011. Abstract A177. doi: https://doi.org/10.1158/1535-7163.TARG-11-A177.

    Article  Google Scholar 

  73. Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, et al. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor. Cancer Lett. 2014;349(1):45–50.

    Article  CAS  PubMed  Google Scholar 

  74. Sato M, Matsuda Y, Wakai T, Kubota M, Osawa M, Fujimaki S, et al. P21-activated kinase-2 is a critical mediator of transforming growth factor-beta-induced hepatoma cell migration. J Gastroenterol Hepatol. 2013;28(6):1047–55. https://doi.org/10.1111/jgh.12150.

    Article  CAS  PubMed  Google Scholar 

  75. Selyunin AS, Sutton SE, Weigele BA, Reddick LE, Orchard RC, Bresson SM, et al. The assembly of a GTPase-kinase signalling complex by a bacterial catalytic scaffold. Nature. 2011;469(7328):107–11. https://doi.org/10.1038/nature09593.

    Article  CAS  PubMed  Google Scholar 

  76. Shu XR, Wu J, Sun H, Chi LQ, Wang JH. PAK4 confers the malignance of cervical cancers and contributes to the cisplatin-resistance in cervical cancer cells via PI3K/AKT pathway. Diagn Pathol. 2015;10:177. https://doi.org/10.1186/s13000-015-0404-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sicard A, Semblat JP, Doerig C, Hamelin R, Moniatte M, Dorin-Semblat D, et al. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cell Microbiol. 2011;13(6):836–45. https://doi.org/10.1111/j.1462-5822.2011.01582.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Siu MKY, Chan HY, Hong DSH, Wong ESY, Wong OGW, Ngan HYS, et al. p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. Proc Natl Acad Sci U S A. 2010a;107(43):18622–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, Tam KF, et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer. 2010b;127(1):21–31. https://doi.org/10.1002/ijc.25005.

    Article  CAS  PubMed  Google Scholar 

  80. Song S, Li X, Guo J, Hao C, Feng Y, Guo B, et al. Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors. Organic Biomolecular Chemistry. 2015a;13(12):3803–18.

    Article  CAS  PubMed  Google Scholar 

  81. Song B, Wang W, Zheng Y, Yang J, Xu Z. P21-activated kinase 1 and 4 were associated with colorectal cancer metastasis and infiltration. J Surg Res. 2015b;196(1):130–5. https://doi.org/10.1016/j.jss.2015.02.035.

    Article  CAS  PubMed  Google Scholar 

  82. Taira N, Nguyen BC, Be Tu PT, Tawata S. Effect of Okinawa propolis on PAK1 activity, Caenorhabditis elegans longevity, Melanogenesis, and growth of Cancer cells. J Agric Food Chem. 2016;64(27):5484–9. https://doi.org/10.1021/acs.jafc.6b01785.

    Article  CAS  PubMed  Google Scholar 

  83. Takao S, Chien W, Madan V, Lin DC, Ding LW, Sun QY, et al. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia. 2017;32:616–25. https://doi.org/10.1038/leu.2017.281.

    Article  CAS  PubMed  Google Scholar 

  84. Viaud J, Peterson JR. An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently. Mol Cancer Ther. 2009;8(9):2559–65. https://doi.org/10.1158/1535-7163.MCT-09-0102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang Y, Gratzke C, Tamalunas A, Wiemer N, Ciotkowska A, Rutz B, et al. P21-activated kinase inhibitors FRAX486 and IPA3: inhibition of prostate stromal cell growth and effects on smooth muscle contraction in the human prostate. PLoS One. 2016;11(4):e0153312. https://doi.org/10.1371/journal.pone.0153312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Williams DS, Carroll PJ, Meggers E. Platinum complex as a nanomolar protein kinase inhibitor. Inorg Chem. 2007;46(8):2944–6. https://doi.org/10.1021/ic062055t.

    Article  CAS  PubMed  Google Scholar 

  87. Wong LE, Chen N, Karantza V, Minden A. The Pak4 protein kinase is required for oncogenic transformation of MDA-MB-231 breast cancer cells. Oncogene. 2013;2:1–6.

    Google Scholar 

  88. Yeo D, Huynh N, Beutler JA, Christophi C, Shulkes A, Baldwin GS, et al. Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases. Cancer Lett. 2014;346(2):264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yeo D, He H, Patel O, Lowy AM, Baldwin GS, Nikfarjam M. FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer. 2016;16(24):24.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Yu W, Kanaan Y, Bae YK, Gabrielson E. Chromosomal changes in aggressive breast cancers with basal-like features. Cancer Genet Cytogenet. 2009;193(1):29–37. doi: S0165–4608(09)00190–3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci. 2005;25(13):3379–88. https://doi.org/10.1523/JNEUROSCI.3553-04.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang HJ, Siu MK, Yeung MC, Jiang LL, Mak VC, Ngan HY, et al. Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma. Carcinogenesis. 2011;32(5):765–71. doi: bgr033 [pii]

    Article  CAS  PubMed  Google Scholar 

  93. Zhang J, Wang J, Guo Q, Want Y, Zhou Y, Peng H, et al. LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells. Cancer Lett. 2012;317(1):24–32.

    Article  CAS  PubMed  Google Scholar 

  94. Zhang J, Zhang H-Y, Wang J, You L-H, Zhou R-Z, Zhao D-M, et al. GL-1196 suppresses the proliferation and invasion of gastric cancer cells via targeting PAK4 and inhibiting PAK4-mediated signaling pathways. International Journal of Molecular Science. 2016;17(14) https://doi.org/10.3390/ijms17040470.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhang HY, Zhang J, Hao CZ, Zhou Y, Wang J, Cheng MS, et al. LC-0882 targets PAK4 and inhibits PAK4-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. Am J Transl Res. 2017;9(6):2736–47.

    PubMed  PubMed Central  Google Scholar 

  96. Zhu Y, Xu L, An H, Liu W, Wang Z, Xu J. p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma. Int J Urol. 2015;22(5):447–53. https://doi.org/10.1111/iju.12715.

    Article  CAS  PubMed  Google Scholar 

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  1. Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Namrata Sampat & Audrey Minden

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  1. Namrata Sampat
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Sampat, N., Minden, A. Inhibitors of the p21 Activated Kinases. Curr Pharmacol Rep 4, 238–249 (2018). https://doi.org/10.1007/s40495-018-0132-7

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