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New Therapeutic Modalities: Transforming Drug Discovery and Development

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Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Abstract

Drug discovery and development has undergone an impressive transformation over recent years driven by the emergence of new chemical modalities. Scientists have seen the expansion of the drug modality toolbox in the strong pursuit of undruggable targets to treat urgent medical needs. As more sophisticated approaches were developed, including new technology innovations to drug delivery, the society has seen the consolidation of novel drug modalities with regulatory approvals of new medicines. In the past 5 years (2018–2022), there has been a rise in the number of Food and Drug Administration (FDA) approvals, including novel modalities beyond the traditional small molecules and biologics. As a result, the field has experienced a boost in different modalities like protein degraders, PROteolysis TArgeting Chimeras (PROTACs), molecular glues, antisense oligonucleotides, small interfering RNA, antibody-drug conjugates, and beyond rule of five molecules. Even within the small-molecule world, exciting new chemical modalities continue to emerge conquering challenging targets, like drugging Kirsten rat sarcoma viral oncogene (KRAS) for the first time. In this chapter, we are describing an overview of the recent breakthroughs leading to marketed drugs within the new therapeutic modalities field.

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References and Further Reading

  • Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL, Lin KP (2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 379:11–21

    Article  CAS  PubMed  Google Scholar 

  • Békés M, Langley DR, Crews CM (2022) PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21:181–200

    Article  PubMed  PubMed Central  Google Scholar 

  • Bjorklund CC, Kang J, Amatangelo M, Polonskaia A, Katz M, Chiu H, Couto S, Wang M, Ren Y, Ortiz M, Towfic F (2020) Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide-and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia 34:1197–1201

    Article  PubMed  Google Scholar 

  • Blanco MJ (2019) Building upon nature’s framework: overview of key strategies toward increasing drug-like properties of natural product cyclopeptides and macrocycles. Cyclic Peptide Design:203–233

    Google Scholar 

  • Blanco MJ, Gardinier KM (2020) New chemical modalities and strategic thinking in early drug discovery. ACS Med Chem Lett 11:228–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, Salituro FG (2018) Breakthroughs in neuroactive steroid drug discovery. Bioorg Med Chem Lett 28:61–70

    Article  CAS  PubMed  Google Scholar 

  • Blanco MJ, Gardinier KM, Namchuk MN (2022) Advancing new chemical modalities into clinical studies. ACS Med Chem Lett 13:1691–1698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caille S, Cui S, Faul MM, Mennen SM, Tedrow JS, Walker SD (2019) Molecular complexity as a driver for chemical process innovation in the pharmaceutical industry. J Organ Chem 84:4583–4603

    Article  CAS  Google Scholar 

  • Chatzigoulas A, Cournia Z (2021) Rational design of allosteric modulators: challenges and successes. Wiley Interdiscipl Rev Comput Molecul Sci 11(6):e1529

    Article  CAS  Google Scholar 

  • Cheng H, Planken S (2018) Precedence and promise of covalent inhibitors of EGFR and KRAS for patients with non-small-cell lung cancer. ACS Med Chem Lett 9:861–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choe S, Wang H, DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Watts JM, Pollyea DA, Fathi AT (2020) Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv 4:1894–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clemow DB, Johnson KW, Hochstetler HM, Ossipov MH, Hake AM, Blumenfeld AM (2020) Lasmiditan mechanism of action–review of a selective 5-HT1F agonist. J Headache Pain 21:1–3

    Article  Google Scholar 

  • Corbett KM, Ford L, Warren DB, Pouton CW, Chalmers DK (2021) Cyclosporin structure and permeability: from A to Z and beyond. J Med Chem 64(13):131–151

    Google Scholar 

  • Desai PV, Raub TJ, Blanco MJ (2012) How hydrogen bonds impact P-glycoprotein transport and permeability. Bioorg Med Chem Lett 22:6540–6548

    Article  CAS  PubMed  Google Scholar 

  • Doak BC, Over B, Giordanetto F, Kihlberg J (2014) Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem Biol 21:1115–1142

    Article  CAS  PubMed  Google Scholar 

  • Dong G, Ding Y, He S, Sheng C (2021) Molecular glues for targeted protein degradation: from serendipity to rational discovery. J Med Chem 64(10):606–620

    Google Scholar 

  • Dubowchik GM, Conway CM, Xin AW (2020) Blocking the CGRP pathway for acute and preventive treatment of migraine: the evolution of success. J Med Chem 63:6600–6623

    Article  CAS  PubMed  Google Scholar 

  • Edmondson SD, Yang B, Fallan C (2019) Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorg Med Chem Lett 29:1555–1564

    Article  CAS  PubMed  Google Scholar 

  • Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, Brown KD, Burgess LE, Burns AC, Burkard MR, Chiang H (2020) Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J Med Chem 63:6679–6693

    Article  CAS  PubMed  Google Scholar 

  • Fiedorczuk K, Chen J (2022) Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Science 378:284–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A, Klippel A (2014) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors I karos and A iolos via modulation of the E 3 ubiquitin ligase complex CRL 4 CRBN. Br J Hematol 164:811–821

    Article  CAS  Google Scholar 

  • Gao S, Wang S, Song Y (2020) Novel immunomodulatory drugs and neo-substrates. Biomarker Res 8:1–8

    Article  Google Scholar 

  • Gerry CJ, Schreiber SL (2020) Unifying principles of bifunctional, proximity-inducing small molecules. Nat Chem Biol 16:369–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han B, Salituro FG, Blanco MJ (2020) Impact of allosteric modulation in drug discovery: Innovation in emerging chemical modalities. ACS Med Chem Lett 11:1810–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen JD, Correa M, Alexander M, Nagy M, Huang D, Sapienza J, Lu G, LeBrun LA, Cathers BE, Zhang W, Tang Y (2021) CC-90009: a cereblon E3 ligase modulating drug that promotes selective degradation of GSPT1 for the treatment of acute myeloid leukemia. J Med Chem 64:1835–1843

    Article  CAS  PubMed  Google Scholar 

  • Hanzl A, Winter GE (2020) Targeted protein degradation: current and future challenges. Curr Opin Chem Biol 56:35–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henning NJ, Boike L, Spradlin JN, Ward CC, Liu G, Zhang E, Belcher BP, Brittain SM, Hesse MJ, Dovala D, McGregor LM (2022) Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol 18:412–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henninot A, Collins JC, Nuss JM (2018) The current state of peptide drug discovery: back to the future? J Med Chem 61:1382–1414

    Article  CAS  PubMed  Google Scholar 

  • Hill MD, Blanco MJ, Salituro FG, Bai Z, Beckley JT, Ackley MA, Dai J, Doherty JJ, Harrison BL, Hoffmann EC, Kazdoba TM (2022) SAGE-718: a first-in-class N-Methyl-d-aspartate receptor positive allosteric modulator for the potential treatment of cognitive impairment. J Med Chem 65:9063–9075

    Article  CAS  PubMed  Google Scholar 

  • Huang L, Guo Z, Wang F, Fu L (2021) KRAS mutation: from undruggable to druggable in cancer. Signal Transduction Target Ther 6:1–20

    Article  Google Scholar 

  • Huang WS, Li F, Gong Y, Zhang Y, Youngsaye W, Xu Y, Zhu X, Greenfield MT, Kohlmann A, Taslimi PM, Toms A (2023) Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non–small cell lung cancer. Bioorg Med Chem Lett 80(129):084

    Google Scholar 

  • Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327:1345–1350

    Article  CAS  PubMed  Google Scholar 

  • Joubert N, Beck A, Dumontet C, Denevault-Sabourin C (2020) Antibody–drug conjugates: the last decade. Pharmaceuticals 13:245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C (2014) Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–305

    Article  PubMed  Google Scholar 

  • Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ (2020) Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem 63(1):52–65

    Article  CAS  PubMed  Google Scholar 

  • Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr (2014) The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–309

    Article  CAS  PubMed  Google Scholar 

  • Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, Belfort GM, Dai J, Loya CM, Ackley MA, Althaus AL, Grossman SJ, Hoffmann E, Doherty JJ, Robichaud AJ (2017) Neuroactive steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1 H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid) A receptor. J Med Chem 60:7810–7819

    Article  CAS  PubMed  Google Scholar 

  • Merrill JT, Werth VP, Furie R, van Vollenhoven R, Dörner T, Petronijevic M, Velasco J, Majdan M, Irazoque-Palazuelos F, Weiswasser M, Korish S (2022) Phase 2 trial of iberdomide in systemic lupus erythematosus. N Engl J Med 386:1034–1045

    Article  CAS  PubMed  Google Scholar 

  • Michot JM, Bouabdallah R, Vitolo U, Doorduijn JK, Salles G, Chiappella A, Zinzani PL, Bijou F, Kersten MJ, Sarmiento R, Mosulen S (2020) Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study. Lancet Hematol 7:e649–e659

    Article  Google Scholar 

  • Mullard A (2021) FDA approves 100th monoclonal antibody product. Nat Rev Drug Discov 20:491–495

    Article  CAS  PubMed  Google Scholar 

  • Nalawansha DA, Crews CM (2020) PROTACs: an emerging therapeutic modality in precision medicine. Cell Chem Biol 27:998–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naylor MR, Bockus AT, Blanco MJ, Lokey RS (2017) Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Curr Opin Chem Biol 38:141–147

    Article  CAS  PubMed  Google Scholar 

  • Naylor MR, Ly AM, Handford MJ, Ramos DP, Pye CR, Furukawa A, Klein VG, Noland RP, Edmondson Q, Turmon AC, Hewitt WM, Schwochert J, Townsend CE, Kelly CN, Blanco MJ, Lokey RS (2018) Lipophilic permeability efficiency reconciles the opposing roles of lipophilicity in membrane permeability and aqueous solubility. J Med Chem 61(11):169–182

    Google Scholar 

  • 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 

  • Petzold G, Fischer ES, Thomä NH (2016) Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532:127–130

    Article  CAS  PubMed  Google Scholar 

  • Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, Cianchetta G, Cai Z, Zhou D, Cui D, Chen P (2018) Discovery of AG-120 (Ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med Chem Lett 9:300–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quemener AM, Bachelot L, Forestier A, Donnou-Fournet E, Gilot D, Galibert MD (2020) The powerful world of antisense oligonucleotides: From bench to bedside. Wiley Interdiscipl Rev RNA 11:e1594

    Article  Google Scholar 

  • Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, Dodd S, Drueckes P, Fabbro D, Gabriel T, Groell JM (2018) Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J Med Chem 61:8120–8135

    Article  CAS  PubMed  Google Scholar 

  • Schreiber SL (2021) The rise of molecular glues. Cell 184:3–9

    Article  CAS  PubMed  Google Scholar 

  • Schwochert J, Lao Y, Pye CR, Naylor MR, Desai PV, Gonzalez Valcarcel IC, Barrett JA, Sawada G, Blanco MJ, Lokey RS (2016) Stereochemistry balances cell permeability and solubility in the naturally derived phepropeptin cyclic peptides. ACS Med Chem Lett 7:757–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talele TT (2020) Opportunities for tapping into three-dimensional chemical space through a quaternary carbon. J Med Chem 63(13):291–315

    Google Scholar 

  • Ting TC, Goralski M, Klein K, Wang B, Kim J, Xie Y, Nijhawan D (2019) Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep 29:1499–1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • US FDA. New drugs at FDA: CDER’s new molecular entities and new therapeutic biological products. https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cdersnew-molecular-entities-and-new-therapeutic-biological-products. Accessed 15 Dec 2022. Imaging or diagnostic entities have been discarded for this analysis

  • Walsh SJ, Bargh JD, Dannheim FM, Hanby AR, Seki H, Counsell AJ, Ou X, Fowler E, Ashman N, Takada Y, Isidro-Llobet A (2021) Site-selective modification strategies in antibody–drug conjugates. Chem Soc Rev 50:1305–1353

    Article  CAS  PubMed  Google Scholar 

  • Wen T, Wang J, Shi Y, Qian H, Liu P (2021) Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia 35:312–332

    Article  CAS  PubMed  Google Scholar 

  • Zaragoza F (2022) Non-covalent albumin ligands in FDA-approved therapeutic peptides and proteins. J Med Chem. Ahead of print. https://doi.org/10.1021/acs.jmedchem.2c01021

  • Zhang D, Blanco MJ, Ying BP, Kohlman D, Liang SX, Victor F, Chen Q, Krushinski J, Filla SA, Hudziak KJ, Mathes BM (2015) Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution from bicyclic to monocyclic cores. Bioorg Med Chem Lett 25:4337–4341

    Article  CAS  PubMed  Google Scholar 

  • Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB (2021) The growth of siRNA-based therapeutics: updated clinical studies. Biochem Pharmacol 189:114432

    Article  CAS  PubMed  Google Scholar 

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Blanco, MJ. (2023). New Therapeutic Modalities: Transforming Drug Discovery and Development. In: Hock, F.J., Gralinski, M.R., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_135-1

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