克服小分子耐药的多维度药物化学策略

Multidimensional Medicinal Chemistry Strategies for Overcoming Small-Molecule Drug Resistance

摘要

耐药性是制约小分子药物疗效的主要障碍，已成为全球公共卫生和肿瘤治疗领域面临的重大难题。系统综述小分子药物耐药的主要机制，包括靶点修饰、旁路信号激活、药物外排增强、酶介导药物失活及细胞表型转化等，并重点阐述针对这些机制的耐药克服策略。相关策略涵盖下一代抑制剂开发、变构抑制、联合治疗、蛋白降解靶向嵌合体技术、外排泵抑制以及抗体药物偶联物等新兴技术。通过整合最新的临床前和临床研究进展，旨在为克服小分子药物耐药提供理论依据和实践指导。

Abstract

Drug resistance is the main obstacle restricting the therapeutic efficacy of small-molecule drugs and has become a major challenge in global public health and cancer treatment. This article systematically reviews the major mechanisms of small-molecule drug resistance, including target modification, bypass signal activation, enhanced drug efflux, enzyme-mediated drug inactivation, and cell phenotypic transformation. It further focuses on the strategies to reverse drug resistance based on the above mechanisms. The relevant strategies include next-generation inhibitor development, allosteric inhibition, combination therapy, proteolysis-targeting chimeras (PROTACs), efflux pump inhibition, and antibody-drug conjugates (ADCs) as emerging technologies. By integrating the latest research advances in preclinical and clinical studies, this article aims to provide a theoretical basis and practical guidance for overcoming small-molecule drug resistance.

关键词

小分子药物 / 耐药 / 核心策略 / 新兴技术

Key words

small-molecule drugs / drug resistance / core strategies / emerging technologies

参考文献

[1] Bognár B, Spohn R, Lázár V. Drug combinations targeting antibiotic resistance[J].NPJ Antimicrob Resist, 2024, 2(1): 29.

[2] Wei J R, Lu M Y, Wei T H,et al. Overcoming cancer therapy resistance: from drug innovation to therapeutics[J].Drug Resist Updat, 2025, 81: 101229.

[3] Vasan N, Baselga J, Hyman D M. A view on drug resistance in cancer[J].Nature, 2019, 575(7782): 299-309.

[4] Ribas A, Wolchok J D. Cancer immunotherapy using checkpoint blockade[J].Science, 2018, 359(6382): 1350-1355.

[5] Ray S, Das S, Suar M. Molecular mechanism of drug resistance[M]//Arora G, Sajid A, Kalia V C.Drug Resistance in Bacteria, Fungi, Malaria, and Cancer. Cham: Springer, 2017: 47-110.

[6] Hu C, Leche C A 2nd, Kiyatkin A,et al. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias[J].Nature, 2022, 602(7897): 518-522.

[7] Tong C W S, Wu W K K, Loong H H F,et al. Drug combination approach to overcome resistance to EGFR tyrosine kinase inhibitors in lung cancer[J].Cancer Lett, 2017, 405: 100-110.

[8] Sun S L, Wu S H, Kang J B,et al. Medicinal chemistry strategies for the development of Bruton’s tyrosine kinase inhibitors against resistance[J].J Med Chem, 2022, 65(11): 7415-7437.

[9] Lee Y, Robbins N, Cowen L E. Molecular mechanisms governing antifungal drug resistance[J].NPJ Antimicrob Resist, 2023, 1(1): 5.

[10] Yoon J, Oh D Y. HER2—targeted therapies beyond breast cancer: an update[J].Nat Rev Clin Oncol, 2024, 21(9): 675-700.

[11] Wolf J, Seto T, Han J Y,et al. Capmatinib in METexon 14—mutated or MET—amplified non—small—cell lung cancer[J].N Engl J Med, 2020, 383(10): 944-957.

[12] Davies H, Bignell G R, Cox C,et al. Mutations of the BRAF gene in human cancer[J].Nature, 2002, 417(6892): 949-954.

[13] Li Q, Li Z, Luo T,et al. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy[J].Mol Biomed, 2022, 3(1): 47.

[14] Finlay M R V, Barton P, Bickerton S,et al. Potent and selective inhibitors of the epidermal growth factor receptor to overcome C797S—mediated resistance[J].J Med Chem, 2021, 64(18): 13704-13718.

[15] Kong X, Pan P, Sun H,et al. Drug discovery targeting anaplastic lymphoma kinase (ALK)[J].J Med Chem, 2019, 62(24): 10927-10954.

[16] Wu P, Clausen M H, Nielsen T E. Allosteric small—molecule kinase inhibitors[J].Pharmacol Ther, 2015, 156: 59-68.

[17] Hochhaus A, Wang J, Kim D W,et al. Asciminib in newly diagnosed chronic myeloid leukemia[J].N Engl J Med, 2024, 391(10): 885-898.

[18] Hoy S M. Deucravacitinib: first approval[J].Drugs, 2022, 82(17): 1671-1679.

[19] Braunwald E, Saberi S, Abraham T P,et al. Mavacamten: a first—in—class myosin inhibitor for obstructive hypertrophic cardiomyopathy[J].Eur Heart J, 2023, 44(44): 4622-4633.

[20] Slosky L M, Caron M G, Barak L S. Biased allosteric modulators: new frontiers in GPCR drug discovery[J].Trends Pharmacol Sci, 2021, 42(4): 283-299.

[21] Sun Q, Wang H, Xie J,et al. Computer—aided drug discovery for undruggable targets[J].Chem Rev, 2025, 125(13): 6309-6365.

[22] Jaaks P, Coker E A, Vis D J,et al. Effective drug combinations in breast, colon and pancreatic cancer cells[J].Nature, 2022, 603(7899): 166-173.

[23] Lovly C M, Shaw A T. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies[J]. Clin Cancer Res, 2014, 20(9): 2249-2256.

[24] Sargianou M, Stathopoulos P, Vrysis C,et al. New β—lactam/β—lactamase inhibitor combination antibiotics[J].Pathogens, 2025, 14(4): 307.

[25] Cho J C, Zmarlicka M T, Shaeer K M,et al. Meropenem/vaborbactam, the first carbapenem/β—lactamase inhibitor combination[J].Ann Pharmacother, 2018, 52(8): 769-779.

[26] Löscher W. Single—target versus multi—target drugs versus combinations of drugs with multiple targets: preclinical and clinical evidence for the treatment or prevention of epilepsy[J].Front Pharmacol, 2021, 12: 730257.

[27] Kabir A, Muth A. Polypharmacology: the science of multi—targeting molecules[J].Pharmacol Res, 2022, 176: 106055.

[28] Ryszkiewicz P, Malinowska B, Schlicker E. Polypharmacology: new drugs in 2023—2024[J].Pharmacol Rep, 2025, 77(3): 543-560.

[29] Abdelsayed M. AI—driven polypharmacology in small—molecule drug discovery[J].Int J Mol Sci, 2025, 26(14): 6996.

[30] Munson B P, Chen M, Bogosian A,et al. De novogeneration of multi—target compounds using deep generative chemistry[J].Nat Commun, 2024, 15(1): 3636.

[31] Ai C, Yang H, Liu X,et al. MTMol—GPT: de novomulti—target molecular generation with transformer—based generative adversarial imitation learning[J].PLoS Comput Biol, 2024, 20(6): e1012229.

[32] Ibrahim S, Umer Khan M, Khurram I,et al. Navigating PROTACs in cancer therapy: advancements, challenges, and future horizons[J].Food Sci Nutr, 2025, 13(2): e70011.

[33] Meloni V, Halstenberg L, Mareczek L,et al. Exploring orodispersible films containing the proteolysis targeting ChimeraARV—110 in hot melt extrusion and solvent casting using polyvinyl alcohol[J].Pharmaceutics, 2024, 16(12): 1499.

[34] Zhu X, Liu W, Tang X,et al. The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS—STING in response to light damage[J].J Neuroinflammation, 2023, 20(1): 119.

[35] Ibne Shoukani H, Nisa S, Bibi Y,et al. Green synthesis of polyethylene glycol coated, ciprofloxacin loaded CuO nanoparticles and its antibacterial activity againstStaphylococcus aureus[J].Sci Rep, 2024, 14(1): 21246.

[36] Tang X, Cui K, Lu X,et al. A novel hypoxia—inducible factor 1α inhibitor KC7F2 attenuates oxygen—induced retinal neovascularization[J].Invest Ophthalmol Vis Sci, 2022, 63(6): 13.

[37] Eloranta K, Pihlajoki M, Liljeström E,et al. SLC—0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration[J].Front Oncol, 2023, 13: 1118268.

[38] Yamazaki T, Gunderson A J, Gilchrist M,et al. Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single—arm, phase 2 trial[J].Lancet Oncol, 2022, 23(9): 1189-1200.

[39] Balog A, Lin T A, Maley D,et al. Preclinical characterization of linrodostat mesylate, a novel, potent, and selective oral indoleamine 2, 3—dioxygenase 1 inhibitor[J].Mol Cancer Ther, 2021, 20(3): 467-476.

[40] Lamb Y N. Pexidartinib: first approval[J].Drugs, 2019, 79(16): 1805-1812.

[41] Deeks E D, Keating G M. Sunitinib[J].Drugs, 2006, 66(17): 2255-2266.

[42] Arora S, Surakiatchanukul T, Arora T,et al. Sildenafil in ophthalmology: an update[J].Surv Ophthalmol, 2022, 67(2): 463-487.

[43] Wang J, Wang P, Zeng Z,et al. Trabectedin in cancers: mechanisms and clinical applications[J].Curr Pharm Des, 2022, 28(24): 1949-1965.

[44] Solárová Z, Mojžiš J, Solár P. Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (review)[J].Int J Oncol, 2015, 46(3): 907-926.

[45] Dixon S J, Olzmann J A. The cell biology of ferroptosis[J].Nat Rev Mol Cell Biol, 2024, 25(6): 424-442.

[46] Abramson J, Adler J, Dunger J,et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3[J].Nature, 2024, 630(8016): 493-500.

[47] Chen J, Bolhuis D L, Laggner C,et al. AtomNet—aided OTUD7B inhibitor discovery and validation[J].Cancers, 2023, 15(2): 517.

[48] McNutt A T, Li Y, Meli R,et al. GNINA 1.3: the next increment in molecular docking with deep learning[J].J Cheminform, 2025, 17(1): 28.

[49] Xu Z, Ren F, Wang P,et al. A generative AI—discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial[J].Nat Med, 2025, 31(8): 2602-2610.

[50] Paul D, Sanap G, Shenoy S,et al. Artificial intelligence in drug discovery and development[J].Drug Discov Today, 2021, 26(1): 80-93.

[51] Oleinikovas V, Gainza P, Ryckmans T,et al. From thalidomide to rational molecular glue design for targeted protein degradation[J].Annu Rev Pharmacol Toxicol, 2024, 64: 291-312.

[52] Toriki E S, Papatzimas J W, Nishikawa K,et al. Rational chemical design of molecular glue degraders[J].ACS Cent Sci, 2023, 9(5): 915-926.

[53] Domostegui A, Nieto—Barrado L, Perez—Lopez C,et al. Chasing molecular glue degraders: screening approaches[J].Chem Soc Rev, 2022, 51(13): 5498-5517.

[54] Xia Y, Sun M, Huang H,et al. Drug repurposing for cancer therapy[J].Sig Transduct Target Ther, 2024, 9: 92.

[55] Jampilek J. Drug repurposing to overcome microbial resistance[J].Drug Discov Today, 2022, 27(7): 2028-2041.

[56] Jiang W, Hu J W, He X R,et al. Statins: a repurposed drug to fight cancer[J].J Exp Clin Cancer Res, 2021, 40(1): 241.

[57] Gundersen E T, Wang Z, Førde J L,et al. Repurposing chlorpromazine for anti—leukaemic therapy with the drug—in—cyclodextrin—in—liposome nanocarrier platform[J].Carbohydr Polym, 2025, 358: 123478.

[58] Bąk U, Krupa A. Challenges and opportunities for celecoxib repurposing[J].Pharm Res, 2023, 40(10): 2329-2345.

[59] Nada H, Choi Y, Kim S,et al. New insights into protein—protein interaction modulators in drug discovery and therapeutic advance[J].Signal Transduct Target Ther, 2024, 9: 341.

[60] Wang F, Yang Z, Wu Y,et al. Menin—MLL protein—protein interaction inhibitors: a patent review (2021—present)[J].Expert Opin Ther Pat, 2025, 35(1): 65-78.

[61] Schopf F H, Biebl M M, Buchner J. The HSP90 chaperone machinery[J].Nat Rev Mol Cell Biol, 2017, 18(6): 345-360.

[62] Zhang L, Liu W, Zheng Z,et al. Allosteric CDC37 inhibitor disrupts chaperone complex to block CDK4/6 maturation[J].Angew Chem Int Ed Engl, 2025, 64(2): e202413618.

[63] Gu C, Wang Y, Zhang L,et al. AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma[J].J Exp Clin Cancer Res, 2022, 41(1): 11.

[64] Sparbier C E, Gillespie A, Gomez J,et al. Targeting Menin disrupts the KMT2A/Band polycomb balance to paradoxically activate bivalent genes[J].Nat Cell Biol, 2023, 25(2): 258-272.

[65] Ji X, Nielsen A L, Heinis C. Cyclic peptides for drug development[J].Angew Chem Int Ed Engl, 2024, 63(3): e202308251.

[66] Fu Z, Li S, Han S,et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy[J].Signal Transduct Target Ther, 2022, 7: 93.

[67] Ahn M J, Tanaka K, Paz—Ares L,et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non—small cell lung cancer: the randomized, open—label phase III TROPION—Lung01 study[J].J Clin Oncol, 2025, 43(3): 260-272.

[68] Wang Y, Guo C, Li W. Artificial intelligence in antibody—drug conjugate development[J].Trends Pharmacol Sci, 2025, 46(12): 1209-1223.

基金资助

国家自然科学基金资助项目(82574235)

国家自然科学基金资助项目(82373710)