Research advances in small-molecule hydrophobic tagging protein degraders
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摘要:
近年来,诱导靶标蛋白降解的小分子靶向蛋白降解剂发展迅速,该类分子由于能够克服传统小分子抑制剂不能应用于难成药靶标、易发耐药等问题而引起了人们极大的兴趣。其中小分子疏水标签蛋白降解剂(hydrophobic tags, HyTs)相较于其他靶向蛋白降解分子,具有更少的氢键供体/受体数量、更小的相对分子质量和较佳的药动学特性,引起了研究人员的广泛关注。本综述着重介绍了疏水标签蛋白降解剂所涉及的可能作用机制及较为热门的疏水标签类型,特别针对金刚烷这一典型的疏水标签,在癌症、神经退行性疾病等领域中的应用进行了详细介绍。但总的来讲,疏水标签目前还存在类型少、降解机制研究不够深入等问题,仍需科研人员进一步地探索,希望本综述能够对此提供有价值的参考信息。
Abstract:In In recent years, small-molecule targeted protein degraders inducing protein degradation have been developing rapidly. These molecules are attracting substantial interest from researchers since they can overcome such limitations of traditional small-molecule inhibitors as their inapplicability to ‘undruggable’ targets and tendency to induce drug resistance. Compared with other targeted protein degraders, small-molecule hydrophobic tags (HyTs) may have a smaller number of hydrogen bond donors/acceptors, smaller molecular weights, and better pharmacokinetic profiles, thus attracting extensive attention from researchers. This review focuses on the possible mechanisms and popular types of HyTs, with special attention to the potential application value of adamantane, a typical hydrophobic tag, in the fields of cancer and neurodegeneration. In general, there are still some problems like fewer types of hydrophobic tags and insufficient research on degradation mechanisms, which still need to be further explored. This review is expected to provide researchers working in the fields of small-molecule targeted protein degraders with some valuable reference.
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Keywords:
- hydrophobic tag /
- targeted protein degradation /
- adamantane /
- cancer
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[1] Adjei AA. What is the right dose?The elusive optimal biologic dose in phase I clinical trials[J]. J Clin Oncol, 2006, 24(25): 4054-4055. doi: 10.1200/JCO.2006.07.4658
[2] Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies[J]. J Clin Oncol, 2013, 31(1): 88-94. doi: 10.1200/JCO.2012.42.7906
[3] Hopkins AL, Groom CR. The druggable genome[J]. Nat Rev Drug Discov, 2002, 1(9): 727-730. doi: 10.1038/nrd892
[4] Campbell J, Ryan CJ, Brough R, et al. Large-scale profiling of kinase dependencies in cancer cell lines[J]. Cell Rep, 2016, 14(10): 2490-2501. doi: 10.1016/j.celrep.2016.02.023
[5] Vaquer-Alicea J, Diamond MI. Propagation of protein aggregation in neurodegenerative diseases[J]. Annu Rev Biochem, 2019, 88: 785-810. doi: 10.1146/annurev-biochem-061516-045049
[6] Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs[J]. Pharmacol Ther, 2017, 174: 138-144. doi: 10.1016/j.pharmthera.2017.02.027
[7] Słabicki M, Kozicka Z, Petzold G, et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K[J]. Nature, 2020, 585(7824): 293-297. doi: 10.1038/s41586-020-2374-x
[8] Gustafson JL, Neklesa TK, Cox CS, et al. Small-molecule-mediated degradation of the androgen receptor through hydrophobic tagging[J]. Angew Chem Int Ed, 2015, 54(33): 9659-9662. doi: 10.1002/anie.201503720
[9] Li ZY, Zhu CG, Ding Y, et al. ATTEC: a potential new approach to target proteinopathies[J]. Autophagy, 2020, 16(1): 185-187. doi: 10.1080/15548627.2019.1688556
[10] Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: cargo-specific degraders using selective autophagy[J]. Mol Cell, 2019, 76 (5): 797-810. e10.
[11] Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins[J]. Nature, 2020, 584(7820): 291-297. doi: 10.1038/s41586-020-2545-9
[12] Kannan MP, Sreeraman S, Somala CS, et al. Advancement of targeted protein degradation strategies as therapeutics for undruggable disease targets[J]. Future Med Chem, 2023, 15(10): 867-883. doi: 10.4155/fmc-2023-0072
[13] Jia XJ, Han X. Targeting androgen receptor degradation with PROTACs from bench to bedside[J]. Biomed Pharmacother, 2023, 158: 114112. doi: 10.1016/j.biopha.2022.114112
[14] Petrylak DP, Stewart TF, Gao X, et al. A phase 2 expansion study of ARV-766, a PROTACandrogen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC)[J]. J Clin Oncol, 2023, 41(6_suppl): TPS290. doi: 10.1200/JCO.2023.41.6_suppl.TPS290
[15] Cantrill C, Chaturvedi P, Rynn C, et al. Fundamental aspects of DMPK optimization of targeted protein degraders[J]. Drug Discov Today, 2020, 25(6): 969-982. doi: 10.1016/j.drudis.2020.03.012
[16] Xie SW, Zhu JJ, Li JD, et al. Small-molecule hydrophobic tagging: a promising strategy of druglike technology for targeted protein degradation[J]. J Med Chem, 2023, 66(16): 10917-10933. doi: 10.1021/acs.jmedchem.3c00736
[17] Shi YT, Long MJ, Rosenberg MM, et al. Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome[J]. ACS Chem Biol, 2016, 11(12): 3328-3337. doi: 10.1021/acschembio.6b00656
[18] Go A, Jang JW, Lee W, et al. Augmentation of the antitumor effects of PARP inhibitors in triple-negative breast cancer via degradation by hydrophobic tagging modulation[J]. Eur J Med Chem, 2020, 204: 112635. doi: 10.1016/j.ejmech.2020.112635
[19] Hachisu M, Seko A, Daikoku S, et al. Hydrophobic tagged dihydrofolate reductase for creating misfolded glycoprotein mimetics[J]. ChemBioChem, 2016, 17(4): 300-303. doi: 10.1002/cbic.201500595
[20] Xie SW, Zhan FY, Zhu JJ, et al. Discovery of norbornene as a novel hydrophobic tag applied in protein degradation[J]. Angew Chem Int Ed, 2023, 62(13): e202217246. doi: 10.1002/anie.202217246
[21] Hershko A, Ciechanover A. The ubiquitin system[J]. Annu Rev Biochem, 1998, 67: 425-479. doi: 10.1146/annurev.biochem.67.1.425
[22] Dong GQ, Ding Y, He SP, et al. Molecular glues for targeted protein degradation: from serendipity to rational discovery[J]. J Med Chem, 2021, 64(15): 10606-10620. doi: 10.1021/acs.jmedchem.1c00895
[23] Luh LM, Scheib U, Juenemann K, et al. Prey for the proteasome: targeted protein degradation-a medicinal chemist’s perspective[J]. Angew Chem Int Ed, 2020, 59(36): 15448-15466. doi: 10.1002/anie.202004310
[24] Ha S, Zhu JC, Xiang H, et al. Hydrophobic tag tethering degrader as a promising paradigm of protein degradation: past, present and future perspectives[J]. Chin Chem Lett, 2024, 35(8): 109192. doi: 10.1016/j.cclet.2023.109192
[25] Shiber A, Breuer W, Brandeis M, et al. Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting[J]. Mol Biol Cell, 2013, 24(13): 2076-2087. doi: 10.1091/mbc.e13-01-0010
[26] Neklesa TK, Tae HS, Schneekloth AR, et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins[J]. Nat Chem Biol, 2011, 7(8): 538-543. doi: 10.1038/nchembio.597
[27] Gandullo-Sánchez L, Ocaña A, Pandiella A. HER3 in cancer: from the bench to the bedside[J]. J Exp Clin Cancer Res, 2022, 41(1): 310. doi: 10.1186/s13046-022-02515-x
[28] Haikala HM, Jänne PA. Thirty years of HER3: from basic biology to therapeutic interventions[J]. Clin Cancer Res, 2021, 27(13): 3528-3539. doi: 10.1158/1078-0432.CCR-20-4465
[29] Uliano J, Corvaja C, Curigliano G, et al. Targeting HER3 for cancer treatment: a new horizon for an old target[J]. ESMO Open, 2023, 8(1): 100790. doi: 10.1016/j.esmoop.2023.100790
[30] Xie T, Lim SM, Westover KD, et al. Pharmacological targeting of the pseudokinase Her3[J]. Nat Chem Biol, 2014, 10(12): 1006-1012. doi: 10.1038/nchembio.1658
[31] Lim SM, Xie T, Westover KD, et al. Development of small molecules targeting the pseudokinase Her3[J]. Bioorg Med Chem Lett, 2015, 25(16): 3382-3389. doi: 10.1016/j.bmcl.2015.04.103
[32] Duan R, Du WF, Guo WJ. EZH2: a novel target for cancer treatment[J]. J Hematol Oncol, 2020, 13(1): 104. doi: 10.1186/s13045-020-00937-8
[33] Liu YK, Yang Q. The roles of EZH2 in cancer and its inhibitors[J]. Med Oncol, 2023, 40(6): 167. doi: 10.1007/s12032-023-02025-6
[34] Wang C, Chen XY, Liu XC, et al. Discovery of precision targeting EZH2 degraders for triple-negative breast cancer[J]. Eur J Med Chem, 2022, 238: 114462. doi: 10.1016/j.ejmech.2022.114462
[35] Ma AQ, Stratikopoulos E, Park KS, et al. Discovery of a first-in-class EZH2 selective degrader[J]. Nat Chem Biol, 2020, 16(2): 214-222. doi: 10.1038/s41589-019-0421-4
[36] McKay RR, Kwak L, Crowdis JP, et al. Phase II multicenter study of enzalutamide in metastatic castration-resistant prostate cancer to identify mechanisms driving resistance[J]. Clin Cancer Res, 2021, 27(13): 3610-3619. doi: 10.1158/1078-0432.CCR-20-4616
[37] Snyder LB, Neklesa TK, Chen X, et al. Abstract 43: discovery of ARV-110, a first-in-class androgen receptor degrading PROTAC for the treatment of men with metastatic castration-resistant prostate cancer[J]. Cancer Res, 2021, 81(13_Suppl): 43. doi: 10.1158/1538-7445.AM2021-43
[38] Shariati M, Meric-Bernstam F. Targeting AKT for cancer therapy[J]. Expert Opin Investig Drugs, 2019, 28(11): 977-988. doi: 10.1080/13543784.2019.1676726
[39] Revathidevi S, Munirajan AK. Akt in cancer: mediator and more[J]. Semin Cancer Biol, 2019, 59: 80-91. doi: 10.1016/j.semcancer.2019.06.002
[40] Gonzalez E, McGraw TE. The Akt kinases: isoform specificity in metabolism and cancer[J]. Cell Cycle, 2009, 8(16): 2502-2508. doi: 10.4161/cc.8.16.9335
[41] Xu F, Zhang X, Chen ZP, et al. Discovery of isoform-selective Akt3 degraders overcoming osimertinib-induced resistance in non-small cell lung cancer cells[J]. J Med Chem, 2022, 65(20): 14032-14048. doi: 10.1021/acs.jmedchem.2c01246
[42] Shiroma Y, Takahashi RU, Yamamoto Y, et al. Targeting DNA binding proteins for cancer therapy[J]. Cancer Sci, 2020, 111(4): 1058-1064. doi: 10.1111/cas.14355
[43] Qin H, Ni HW, Liu YC, et al. RNA-binding proteins in tumor progression[J]. J Hematol Oncol, 2020, 13(1): 90. doi: 10.1186/s13045-020-00927-w
[44] Bonczek O, Wang LX, Gnanasundram SV, et al. DNA and RNA binding proteins: from motifs to roles in cancer[J]. Int J Mol Sci, 2022, 23(16): 9329. doi: 10.3390/ijms23169329
[45] Wang Y, Zhang JZ, Deng JF, et al. Targeted degradation of DNA/RNA binding proteins via covalent hydrophobic tagging[J]. CCS Chem, 2023, 5(10): 2207-2214. doi: 10.31635/ccschem.023.202302873
[46] Giovannini J, Smeralda W, Jouanne M, et al. Tau protein aggregation: key features to improve drug discovery screening[J]. Drug Discov Today, 2022, 27(5): 1284-1297. doi: 10.1016/j.drudis.2022.01.009
[47] Zhang HQ, Wei W, Zhao M, et al. Interaction between aβ and tau in the pathogenesis of Alzheimer’s disease[J]. Int J Biol Sci, 2021, 17(9): 2181-2192. doi: 10.7150/ijbs.57078
[48] Gao N, Chu TT, Li QQ, et al. Hydrophobic tagging-mediated degradation of Alzheimer’s disease related Tau[J]. RSC Adv, 2017, 7(64): 40362-40366. doi: 10.1039/C7RA05347A
[49] Barmada SJ, Skibinski G, Korb E, et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis[J]. J Neurosci, 2010, 30(2): 639-649. doi: 10.1523/JNEUROSCI.4988-09.2010
[50] de Boer EMJ, Orie VK, Williams T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases[J]. J Neurol Neurosurg Psychiatry, 2020, 92(1): 86-95.
[51] Gao N, Huang YP, Chu TT, et al. TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides[J]. Bioorg Chem, 2019, 84: 254-259. doi: 10.1016/j.bioorg.2018.11.042
[52] Boland B, Yu WH, Corti O, et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of aging[J]. Nat Rev Drug Discov, 2018, 17(9): 660-688. doi: 10.1038/nrd.2018.109
[53] Tabrizi SJ, Flower MD, Ross CA, et al. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities[J]. Nat Rev Neurol, 2020, 16(10): 529-546. doi: 10.1038/s41582-020-0389-4
[54] Hirai K, Yamashita H, Tomoshige S, et al. Conversion of a PROTAC mutant huntingtin degrader into small-molecule hydrophobic tags focusing on drug-like properties[J]. ACS Med Chem Lett, 2022, 13(3): 396-402. doi: 10.1021/acsmedchemlett.1c00500
[55] Los GV, Encell LP, McDougall MG, et al. HaloTag: a novel protein labeling technology for cell imaging and protein analysis[J]. ACS Chem Biol, 2008, 3(6): 373-382. doi: 10.1021/cb800025k
[56] England CG, Luo HM, Cai WB. HaloTag technology: a versatile platform for biomedical applications[J]. Bioconjug Chem, 2015, 26(6): 975-986. doi: 10.1021/acs.bioconjchem.5b00191
[57] Chen WY, Younis MH, Zhao ZK, et al. Recent biomedical advances enabled by HaloTag technology[J]. Biocell, 2022, 46(8): 1789-1801. doi: 10.32604/biocell.2022.018197
[58] Tae HS, Sundberg TB, Neklesa TK, et al. Identification of hydrophobic tags for the degradation of stabilized proteins[J]. ChemBioChem, 2012, 13(4): 538-541. doi: 10.1002/cbic.201100793
[59] Long MJ, Gollapalli DR, Hedstrom L. Inhibitor mediated protein degradation[J]. Chem Biol, 2012, 19(5): 629-637. doi: 10.1016/j.chembiol.2012.04.008
[60] Singh RR, Reindl KM. Glutathione S-transferases in cancer[J]. Antioxidants, 2021, 10(5): 701. doi: 10.3390/antiox10050701
[61] Slade D. PARP and PARG inhibitors in cancer treatment[J]. Genes Dev, 2020, 34(5/6): 360-394.
[62] Rose M, Burgess JT, O’Byrne K, et al. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance[J]. Front Cell Dev Biol, 2020, 8: 564601. doi: 10.3389/fcell.2020.564601
[63] Griguolo G, Dieci MV, Miglietta F, et al. Olaparib for advanced breast cancer[J]. Future Oncol, 2020, 16(12): 717-732. doi: 10.2217/fon-2019-0689
[64] He QD, Zhao XF, Wu DL, et al. Hydrophobic tag-based protein degradation: development, opportunity and challenge[J]. Eur J Med Chem, 2023, 260: 115741. doi: 10.1016/j.ejmech.2023.115741
[65] Anshabo AT, Milne R, Wang SD, et al. CDK9: a comprehensive review of its biology, and its role as a potential target for anti-cancer agents[J]. Front Oncol, 2021, 11: 678559. doi: 10.3389/fonc.2021.678559
[66] Chen ZS, Yang DH. Protein kinase inhibitors as sensitizing agents for chemotherapy [M]. New York: Academic Press, 2019: 125-149.
[67] Li JC, Liu T, Song YL, et al. Discovery of small-molecule degraders of the CDK9-cyclin T1 complex for targeting transcriptional addiction in prostate cancer[J]. J Med Chem, 2022, 65(16): 11034-11057. doi: 10.1021/acs.jmedchem.2c00257
[68] Wu TZ, Qin Z, Tian YC, et al. Recent developments in the biology and medicinal chemistry of CDK9 inhibitors: an update[J]. J Med Chem, 2020, 63(22): 13228-13257. doi: 10.1021/acs.jmedchem.0c00744
[69] Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases[J]. Cell, 2010, 141(7): 1117-1134. doi: 10.1016/j.cell.2010.06.011
[70] Xie SW, Sun Y, Liu YL, et al. Development of alectinib-based PROTACs as novel potent degraders of anaplastic lymphoma kinase (ALK)[J]. J Med Chem, 2021, 64(13): 9120-9140. doi: 10.1021/acs.jmedchem.1c00270