Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Perspective

New Frontiers in the Discovery and Development of PROTACs

Author(s): Samir H. Barghout*

Volume 22, Issue 15, 2022

Published on: 25 May, 2022

Page: [2656 - 2661] Pages: 6

DOI: 10.2174/1871520622666220412132759

Abstract

Proteolysis targeting chimeras (PROTACs) are an emerging class of targeted protein degraders that coopt the intracellular degradation machinery to selectively deplete their respective targets. PROTACs act as bifunctional degraders that comprise ubiquitin E3 ligase- and target-binding moieties connected by chemical linkers with appropriate physicochemical properties. Through this bivalent structure, PROTACs induce the degradation of their targets via proximity-based pharmacology. Compared to conventional inhibitors, PROTACs exhibit superior pharmacologic properties in terms of efficacy, potency, selectivity, the durability of response, and efficacy against undruggable proteins. Over the last few years, the scientific community has witnessed significant endeavors to advance this field and expand the armamentarium of PROTACs. In this perspective, we highlight these advances with an emphasis on emerging PROTAC variants, PROTACtability and degradability of protein targets, expression-guided PROTACs, multivalent PROTACs, preclinical resistance, candidates evaluated in clinical trials, and prospects for the use of PROTACs as a therapeutic modality.

Keywords: PROTACs, targeted protein degradation, LYTACs, MADTACs, PROTACtability, degradability, expression-guided PROTACs, trivalent PROTACs.

« Previous Next »
Graphical Abstract

[1]
Barghout, S.H. Targeted protein degradation: An emerging therapeutic strategy in cancer. Anticancer. Agents Med. Chem., 2021, 21(2), 214-230.
[http://dx.doi.org/10.2174/1871520620666200410082652] [PMID: 32275492]
[2]
Tomoshige, S.; Ishikawa, M. PROTACs and other chemical protein degradation technologies for the treatment of neurodegenerative disor-ders. Angew. Chem. Int. Ed. Engl., 2021, 60(7), 3346-3354.
[http://dx.doi.org/10.1002/anie.202004746] [PMID: 32410219]
[3]
Dale, B.; Cheng, M.; Park, K-S.; Kaniskan, H.Ü.; Xiong, Y.; Jin, J. Advancing targeted protein degradation for cancer therapy. Nat. Rev. Cancer, 2021, 21(10), 638-654.
[http://dx.doi.org/10.1038/s41568-021-00365-x] [PMID: 34131295]
[4]
Kostic, M.; Jones, L.H. Critical assessment of targeted protein degradation as a research tool and pharmacological modality. Trends Pharmacol. Sci., 2020, 41(5), 305-317.
[http://dx.doi.org/10.1016/j.tips.2020.02.006] [PMID: 32222318]
[5]
Burslem, G.M.; Crews, C.M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 2020, 181(1), 102-114.
[http://dx.doi.org/10.1016/j.cell.2019.11.031] [PMID: 31955850]
[6]
Mizushima, N.; Levine, B. Autophagy in human diseases. N. Engl. J. Med., 2020, 383(16), 1564-1576.
[http://dx.doi.org/10.1056/NEJMra2022774] [PMID: 33053285]
[7]
Alabi, S.B.; Crews, C.M. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J. Biol. Chem., 2021, 296, 100647.
[http://dx.doi.org/10.1016/j.jbc.2021.100647] [PMID: 33839157]
[8]
Takahashi, D.; Arimoto, H. Selective autophagy as the basis of autophagy-based degraders. Cell Chem. Biol., 2021, 28(7), 1061-1071.
[http://dx.doi.org/10.1016/j.chembiol.2021.05.006] [PMID: 34087173]
[9]
Takahashi, D.; Arimoto, H. Targeting selective autophagy by AUTAC degraders. Autophagy, 2020, 16(4), 765-766.
[http://dx.doi.org/10.1080/15548627.2020.1718362] [PMID: 31958028]
[10]
Takahashi, D.; Moriyama, J.; Nakamura, T.; Miki, E.; Takahashi, E.; Sato, A.; Akaike, T.; Itto-Nakama, K.; Arimoto, H. AUTACs: Cargo-specific degraders using selective autophagy. Mol. Cell, 2019, 76(5), 797-810.e10.
[http://dx.doi.org/10.1016/j.molcel.2019.09.009] [PMID: 31606272]
[11]
Li, Z.; Zhu, C.; Ding, Y.; Fei, Y.; Lu, B. ATTEC: A potential new approach to target proteinopathies. Autophagy, 2020, 16(1), 185-187.
[http://dx.doi.org/10.1080/15548627.2019.1688556] [PMID: 31690177]
[12]
Banik, S.M.; Pedram, K.; Wisnovsky, S.; Ahn, G.; Riley, N.M.; Bertozzi, C.R. Lysosome-targeting chimaeras for degradation of extracellu-lar proteins. Nature, 2020, 584(7820), 291-297.
[http://dx.doi.org/10.1038/s41586-020-2545-9] [PMID: 32728216]
[13]
Caianiello, D.F.; Zhang, M.; Ray, J.D.; Howell, R.A.; Swartzel, J.C.; Branham, E.M.J.; Chirkin, E.; Sabbasani, V.R.; Gong, A.Z.; McDonald, D.M.; Muthusamy, V.; Spiegel, D.A. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat. Chem. Biol., 2021, 17(9), 947-953.
[http://dx.doi.org/10.1038/s41589-021-00851-1] [PMID: 34413525]
[14]
Schneider, M.; Radoux, C.J.; Hercules, A.; Ochoa, D.; Dunham, I.; Zalmas, L.P.; Hessler, G.; Ruf, S.; Shanmugasundaram, V.; Hann, M.M.; Thomas, P.J.; Queisser, M.A.; Benowitz, A.B.; Brown, K.; Leach, A.R. The PROTACtable genome. Nat. Rev. Drug Discov., 2021, 20(10), 789-797.
[http://dx.doi.org/10.1038/s41573-021-00245-x] [PMID: 34285415]
[15]
Donovan, K.A.; Ferguson, F.M.; Bushman, J.W.; Eleuteri, N.A.; Bhunia, D.; Ryu, S.; Tan, L.; Shi, K.; Yue, H.; Liu, X.; Dobrovolsky, D.; Jiang, B.; Wang, J.; Hao, M.; You, I.; Teng, M.; Liang, Y.; Hatcher, J.; Li, Z.; Manz, T.D.; Groendyke, B.; Hu, W.; Nam, Y.; Sengupta, S.; Cho, H.; Shin, I.; Agius, M.P.; Ghobrial, I.M.; Ma, M.W.; Che, J.; Buhrlage, S.J.; Sim, T.; Gray, N.S.; Fischer, E.S. Mapping the degradable kinome provides a resource for expedited degrader development. Cell, 2020, 183(6), 1714-1731.
[16]
Deshaies, R.J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature, 2020, 580(7803), 329-338.
[http://dx.doi.org/10.1038/s41586-020-2168-1] [PMID: 32296187]
[17]
He, Y.; Zhang, X.; Chang, J.; Kim, H.N.; Zhang, P.; Wang, Y.; Khan, S.; Liu, X.; Zhang, X.; Lv, D.; Song, L.; Li, W.; Thummuri, D.; Yuan, Y.; Wiegand, J.S.; Ortiz, Y.T.; Budamagunta, V.; Elisseeff, J.H.; Campisi, J.; Almeida, M.; Zheng, G.; Zhou, D. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat. Commun., 2020, 11(1), 1996.
[http://dx.doi.org/10.1038/s41467-020-15838-0] [PMID: 32332723]
[18]
Khan, S.; Zhang, X.; Lv, D.; Zhang, Q.; He, Y.; Zhang, P.; Liu, X.; Thummuri, D.; Yuan, Y.; Wiegand, J.S.; Pei, J.; Zhang, W.; Sharma, A.; McCurdy, C.R.; Kuruvilla, V.M.; Baran, N.; Ferrando, A.A.; Kim, Y.M.; Rogojina, A.; Houghton, P.J.; Huang, G.; Hromas, R.; Konopleva, M.; Zheng, G.; Zhou, D. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med., 2019, 25(12), 1938-1947.
[http://dx.doi.org/10.1038/s41591-019-0668-z] [PMID: 31792461]
[19]
Zhang, X.; Crowley, V.M.; Wucherpfennig, T.G.; Dix, M.M.; Cravatt, B.F. Electrophilic PROTACs that degrade nuclear proteins by engag-ing DCAF16. Nat. Chem. Biol., 2019, 15(7), 737-746.
[http://dx.doi.org/10.1038/s41589-019-0279-5] [PMID: 31209349]
[20]
Imaide, S.; Riching, K.M.; Makukhin, N.; Vetma, V.; Whitworth, C.; Hughes, S.J.; Trainor, N.; Mahan, S.D.; Murphy, N.; Cowan, A.D.; Chan, K-H.; Craigon, C.; Testa, A.; Maniaci, C.; Urh, M.; Daniels, D.L.; Ciulli, A. Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity. Nat. Chem. Biol., 2021, 17(11), 1157-1167.
[http://dx.doi.org/10.1038/s41589-021-00878-4] [PMID: 34675414]
[21]
Zheng, M.; Huo, J.; Gu, X.; Wang, Y.; Wu, C.; Zhang, Q.; Wang, W.; Liu, Y.; Liu, Y.; Zhou, X.; Chen, L.; Zhou, Y.; Li, H. Rational design and synthesis of novel dual PROTACs for simultaneous degradation of EGFR and PARP. J. Med. Chem., 2021, 64(11), 7839-7852.
[http://dx.doi.org/10.1021/acs.jmedchem.1c00649] [PMID: 34038131]
[22]
Mayor-Ruiz, C.; Jaeger, M.G.; Bauer, S.; Brand, M.; Sin, C.; Hanzl, A.; Mueller, A.C.; Menche, J.; Winter, G.E. Plasticity of the cullin-ring ligase repertoire shapes sensitivity to ligand-induced protein degradation. Mol. Cell, 2019, 75(4), 849-858.e8.
[http://dx.doi.org/10.1016/j.molcel.2019.07.013] [PMID: 31442425]
[23]
Zhang, L.; Riley-Gillis, B.; Vijay, P.; Shen, Y. Acquired resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol. Cancer Ther., 2019, 18(7), 1302-1311.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-1129] [PMID: 31064868]
[24]
Shirasaki, R.; Matthews, G.M.; Gandolfi, S.; de Matos Simoes, R.; Buckley, D.L.; Raja Vora, J.; Sievers, Q.L.; Brüggenthies, J.B.; Dashev-sky, O.; Poarch, H.; Tang, H.; Bariteau, M.A.; Sheffer, M.; Hu, Y.; Downey-Kopyscinski, S.L.; Hengeveld, P.J.; Glassner, B.J.; Dhimolea, E.; Ott, C.J.; Zhang, T.; Kwiatkowski, N.P.; Laubach, J.P.; Schlossman, R.L.; Richardson, P.G.; Culhane, A.C.; Groen, R.W.J.; Fischer, E.S.; Vazquez, F.; Tsherniak, A.; Hahn, W.C.; Levy, J.; Auclair, D.; Licht, J.D.; Keats, J.J.; Boise, L.H.; Ebert, B.L.; Bradner, J.E.; Gray, N.S.; Mitsiades, C.S. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunc-tional degraders of oncoproteins. Cell Rep., 2021, 34(1), 108532.
[http://dx.doi.org/10.1016/j.celrep.2020.108532] [PMID: 33406420]
[25]
Kurimchak, A.M.; Herrera-Montávez, C.; Montserrat, S.; Araiza, D.; Hu, J.; Jin, J.; Duncan, J.S. MDR1 Drug efflux pump promotes intrin-sic and acquired resistance to PROTACs in cancer cells. bioRxiv, 2021, 2021.2012.2002.470920.
[http://dx.doi.org/10.1101/2021.12.02.470920]
[26]
Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov., 2021, 20(4), 247-250.
[http://dx.doi.org/10.1038/d41573-021-00052-4] [PMID: 33737725]
[27]
Mullard, A. First targeted protein degrader hits the clinic. Nat. Rev. Drug Discov., 2019.
[http://dx.doi.org/10.1038/d41573-019-00043-6] [PMID: 30936511]
[28]
Petrylak, D.P.; Gao, X.; Vogelzang, N.J.; Garfield, M.H.; Taylor, I.; Moore, M.D.; Peck, R.A., III H.A.B., First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) fol-lowing enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol., 2020, 38(15)(Suppl.), 3500-3500.
[http://dx.doi.org/10.1200/JCO.2020.38.15_suppl.3500]
[29]
Mullard, A. Targeted degraders clear first safety hurdles. Nat. Rev. Drug Discov., 2020, 19(7), 435.
[PMID: 32514100]
[30]
Brien, G.L.; Remillard, D.; Shi, J.; Hemming, M.L.; Chabon, J.; Wynne, K.; Dillon, E.T.; Cagney, G.; Van Mierlo, G.; Baltissen, M.P.; Vermeulen, M.; Qi, J.; Fröhling, S.; Gray, N.S.; Bradner, J.E.; Vakoc, C.R.; Armstrong, S.A. Targeted degradation of BRD9 reverses onco-genic gene expression in synovial sarcoma. eLife, 2018, 7, 7.
[http://dx.doi.org/10.7554/eLife.41305] [PMID: 30431433]
[31]
Ishizawa, J.; Zarabi, S.F.; Davis, R.E.; Halgas, O.; Nii, T.; Jitkova, Y.; Zhao, R.; St-Germain, J.; Heese, L.E.; Egan, G.; Ruvolo, V.R.; Bar-ghout, S.H.; Nishida, Y.; Hurren, R.; Ma, W.; Gronda, M.; Link, T.; Wong, K.; Mabanglo, M.; Kojima, K.; Borthakur, G.; MacLean, N.; Ma, M.C.J.; Leber, A.B.; Minden, M.D.; Houry, W.; Kantarjian, H.; Stogniew, M.; Raught, B.; Pai, E.F.; Schimmer, A.D.; Andreeff, M. Mi-tochondrial ClpP-mediated proteolysis induces selective cancer cell lethality. Cancer Cell, 2019, 35(5), 721-737.e9.
[http://dx.doi.org/10.1016/j.ccell.2019.03.014] [PMID: 31056398]

Rights & Permissions Print Cite
Article Metrics
51
1
© 2024 Bentham Science Publishers | Privacy Policy