Targeted Protein Degradation:

Daria       Kotlarek; Agata       Pawlik; Maria       Sagan; Marta       Sowała; Alina       Zawiślak-Architek; Michał   J.    Walczak
doi:10.2174/2213809907666200130111436
Abstract

Targeted Protein Degradation (TPD) is an emerging new modality of drug discovery that offers unprecedented therapeutic benefits over traditional protein inhibition. Most importantly, TPD unlocks the untapped pool of the proteome that to date has been considered undruggable. Captor Therapeutics (Captor) is the fourth global, and first European, company that develops small molecule drug candidates based on the principles of targeted protein degradation. Captor is located in Basel, Switzerland and Wroclaw, Poland and exploits the best opportunities of the two sites – experience and non-dilutive European grants, and talent pool, respectively. Through over $38 M of funding, Captor has been active in three areas of TPD: molecular glues, bi-specific degraders and direct degraders, ObteronsTM.
Keywords: Targeted protein degradation, PROTAC, degraders, proteasome, cancer, oncology.
« Previous Next »
[1] 
Deshaies RJ. Protein degradation: Prime time for PROTACs. Nat Chem Biol  2015; 11(9): 634-5.
[http://dx.doi.org/10.1038/nchembio.1887] [PMID: 26284668] 
[2] 
Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad, Ser B, Phys Biol Sci  2009; 85(1): 12-36.
[http://dx.doi.org/10.2183/pjab.85.12] 
[3] 
Tan X, Calderon-Villalobos LIA, Sharon M, et al. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature  2007; 446(7136): 640-5.
[http://dx.doi.org/10.1038/nature05731] [PMID: 17410169] 
[4] 
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA  2001; 98(15): 8554-9.
[http://dx.doi.org/10.1073/pnas.141230798] [PMID: 11438690] 
[5] 
Scudellari M. Protein-slaying drugs could be the next blockbuster therapies. Nature  2019; 567(7748): 298-300.
[http://dx.doi.org/10.1038/d41586-019-00879-3] [PMID: 30894734] 
[6] 
Kenten JH, Roberts SF. Inventor; PROTEINIX Inc, assignee Controlling protein levels in eucaryotic organisms United States patent US6306663(B1).  2001.
[7] 
Schneekloth AR, Pucheault M, Tae HS, Crews CM. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg Med Chem Lett  2008; 18(22): 5904-8.
[http://dx.doi.org/10.1016/j.bmcl.2008.07.114] [PMID: 18752944] 
[8] 
Toure M, Crews CM. Small-molecule PROTACS: New approaches to protein degradation. Wiley-VCH Verlag  2016; 55: 1966-73.
[9] 
Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science  2017; 355(6330): 1163-7.
[10] 
Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov  2017; 16(2): 101-14.
[http://dx.doi.org/10.1038/nrd.2016.211] 
[11] 
Kargbo RB. PROTAC degradation of IRAK4 for the treatment of neurodegenerative and cardiovascular diseases. ACS Med Chem Lett  2019; 10(9): 1251-2.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00385] [PMID: 31531192] 
[12] 
Lu M, Liu T, Jiao Q, et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur J Med Chem  2018; 146: 251-9.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.063] [PMID: 29407955] 
[13] 
Bondeson DP, Mares A, Smith IED, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol  2015; 11(8): 611-7.
[http://dx.doi.org/10.1038/nchembio.1858] [PMID: 26075522] 
[14] 
Neklesa TK, Winkler JD, Crews CM. Targeted protein degradation by PROTACs. Pharmacol Ther  2017; 174: 138-44.
[http://dx.doi.org/10.1016/j.pharmthera.2017.02.027] [PMID: 28223226] 
[15] 
Lai A, Kahraman M, Govek S, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem  2015; 58(12): 4888-904.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00054] [PMID: 25879485] 
[16] 
Raina K, Lu J, Qian Y, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci USA  2016; 113(26): 7124-9.
[http://dx.doi.org/10.1073/pnas.1521738113] [PMID: 27274052] 
[17] 
Cyrus K, Wehenkel M, Choi EY, Lee H, Swanson H, Kim KB. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem  2010; 5(7): 979-85.
[http://dx.doi.org/10.1002/cmdc.201000146] [PMID: 20512796] 
[18] 
Salami J, Alabi S, Willard RR, et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol  2018; 1(1): 100.
[http://dx.doi.org/10.1038/s42003-018-0105-8] [PMID: 30271980] 
[19] 
Brand M, Jiang B, Bauer S, et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol  2019; 26(2): e300-6.
[http://dx.doi.org/10.1016/j.chembiol.2018.11.006] [PMID: 30595531] 
[20] 
Huang HT, Dobrovolsky D, Paulk J, et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem Biol  2018; 25(1): 88-99.
[http://dx.doi.org/10.1016/j.chembiol.2017.10.005] [PMID: 29129717] 
[21] 
Bondeson DP, Smith BE, Burslem GM, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol  2018; 25(1): 78-87.
[http://dx.doi.org/10.1016/j.chembiol.2017.09.010] [PMID: 29129718] 
[22] 
Mullard A. First targeted protein degrader hits the clinic. Nat Rev Drug Discov  2019; 18: 237-9.
[http://dx.doi.org/10.1038/d41573-019-00043-6] [PMID: 30936511] 
[23] 
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev  2001; 46(1-3): 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830] 
[24] 
Churcher I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones. J Med Chem  2018; 61(2): 444-52.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01272] [PMID: 29144739] 
[25] 
Hayashi K, Tan X, Zheng N, et al. Small-molecule agonists and antagonists of F-box protein-substrate interactions in auxin perception and signaling. Proc Natl Acad Sci USA  2008; 105(14): 5632-7.
[http://dx.doi.org/10.1073/pnas.0711146105] [PMID: 18391211] 
[26] 
Fischer ES, Park E, Eck MJ, Thomä NH. SPLINTS: small-molecule protein ligand interface stabilizers. Curr Opin in Struct Biol  2016; 37: 115-22.
[http://dx.doi.org/10.1016/j.sbi.2016.01.004] [PMID: 26829757] 
[27] 
Che Y, Gilbert AM, Shanmugasundaram V, Noe MC. Inducing protein-protein interactions with molecular glues. Bioorg Med Chem Lett  2018; 28(15): 2585-92.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.046] [PMID: 29980357] 
[28] 
Hughes SJ, Ciulli A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays in Biochem  2017; 61(5): 505-16.
[http://dx.doi.org/10.1042/EBC20170041] 
[29] 
Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer  2004; 4(4): 314-22.
[http://dx.doi.org/10.1038/nrc1323] [PMID: 15057291] 
[30] 
Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med  1999; 341(21): 1565-71.
[http://dx.doi.org/10.1056/NEJM199911183412102] [PMID: 10564685] 
[31] 
Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science  2014; 343(6168): 301-5.
[http://dx.doi.org/10.1126/science.1244851] [PMID: 24292625] 
[32] 
Krönke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature  2015; 523(7559): 183-8.
[http://dx.doi.org/10.1038/nature14610] [PMID: 26131937] 
[33] 
Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J Med Chem  2018; 61(2): 535-42.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01921] [PMID: 28425720] 
[34] 
Hagner PR, Man HW, Fontanillo C, et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood  2015; 126(6): 779-89.
[http://dx.doi.org/10.1182/blood-2015-02-628669] [PMID: 26002965] 
[35] 
Matyskiela ME, Lu G, Ito T, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature  2016; 535(7611): 252-7.
[http://dx.doi.org/10.1038/nature18611] [PMID: 27338790] 
[36] 
Hansen JD, Condroski K, Correa M, et al. Protein degradation via CRL4CRBN ubiquitin ligase: discovery and structure-activity relationships of novel glutarimide analogs that promote degradation of aiolos and/or GSPT1. J Med Chem  2018; 61(2): 492-503.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01911] [PMID: 28358507] 
[37] 
Han T, Goralski M, Gaskill N, et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science  2017; 356(6363): 3755.
[http://dx.doi.org/10.1126/science.aal3755] 
[38] 
Uehara T, Minoshima Y, Sagane K, et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat Chem Biol  2017; 13(6): 675-80.
[http://dx.doi.org/10.1038/nchembio.2363] [PMID: 28437394] 
[39] 
An open-label, randomized, phase ii study of the efficacy and safety of Indisulam (E7070) in combination with Capecitabine. ClinicalTrailsgov  2017. Available from:. https://clinicaltrials.gov/ct2/ show/NCT00165880
[40] 
Gu S, Cui D, Chen X, Xiong X, Zhao Y. PROTACs: An emerging targeting technique for protein degradation in drug discovery. BioEssays  2018; 40(4) e1700247
[41] 
Pei H, Peng Y, Zhao Q, Chen Y. Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery. RSC Advances  2019; 9(30): 16967-76.
[http://dx.doi.org/10.1039/C9RA03423D] 
[42] 
Itoh Y, Ishikawa M, Naito M, Hashimoto Y. Protein knockdown using methyl bestatin-ligand hybrid molecules: design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J Am Chem Soc  2010; 132(16): 5820-6.
[http://dx.doi.org/10.1021/ja100691p] [PMID: 20369832] 
[43] 
Fischer ES, Böhm K, Lydeard JR, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature  2014; 512(7512): 49-53.
[http://dx.doi.org/10.1038/nature13527] [PMID: 25043012] 
[44] 
Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science  2010; 327(5971): 1345-50.
[http://dx.doi.org/10.1126/science.1177319] 
[45] 
Lu J, Qian Y, Altieri M, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol  2015; 22(6): 755-63.
[http://dx.doi.org/10.1016/j.chembiol.2015.05.009] [PMID: 26051217] 
[46] 
Winter GE, Buckley DL, Paulk J, et al. Selective target protein degradation via phthalimide conjugation. Science  2015; 348(6241): 1376-81.
[47] 
Chopra R, Sadok A, Collins I. A critical evaluation of the approaches to targeted protein degradation for drug discovery. Drug Discov Today Technol  2019; 31: 5-13.
[http://dx.doi.org/10.1016/j.ddtec.2019.02.002] 
[48] 
Neklesa TK, Tae HS, Schneekloth AR, et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat Chem Biol  2011; 7(8): 538-43.
[http://dx.doi.org/10.1038/nchembio.597] [PMID: 21725302] 
[49] 
Tellez A. The Case for targeted protein degradation | LinkedIn 2019. Available from:. https://www. linkedin.com/pulse/case-targeted-protein-degradation-andres-tellez/
[50] 
Oo ML, Thangada S, Wu MT, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem  2007; 282(12): 9082-9.
[http://dx.doi.org/10.1074/jbc.M610318200] [PMID: 17237497] 
[51] 
Oo ML, Chang S-H, Thangada S, et al. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest  2011; 121(6): 2290-300.
[http://dx.doi.org/10.1172/JCI45403] [PMID: 21555855] 
[52] 
Valentine WJ, Godwin VI, Osborne DA, et al. FTY720 (Gilenya) phosphate selectivity of sphingosine 1-phosphate receptor subtype 1 (S1P1) G protein-coupled receptor requires motifs in intracellular loop 1 and transmembrane domain 2. J Biol Chem  2011; 286(35): 30513-25.
[http://dx.doi.org/10.1074/jbc.M111.263442] [PMID: 21719706] 
[53] 
Kerres N, Steurer S, Schlager S, et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep  2017; 20(12): 2860-75.
[http://dx.doi.org/10.1016/j.celrep.2017.08.081] [PMID: 28930682] 
[54] 
Bayer and Arvinas unveil targeted protein degradation joint venture, Oerth bio 2019. Available from:. https://www.globenewswire.com/news-release/ 2019/10/01/1923054/0/en/Bayer-and-Arvinas-Unveil-Targeted-Protein-Degradation-Joint-Venture-Oerth-Bio.html
[55] 
Wang P, Zhou J. Proteolysis targeting chimera (PROTAC): a paradigm-shifting approach in small molecule drug discovery. Curr Top Med Chem  2018; 18(16): 1354-6.
[http://dx.doi.org/10.2174/1568026618666181010101922] [PMID: 30306871] 
[56] 
Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, Mallamo JP. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem Neurosci  2012; 3(1): 50-68.
[http://dx.doi.org/10.1021/cn200100h] [PMID: 22267984] 
[57] 
Arvinas to Present Preclinical Tau-Directed PROTAC® protein degrader data. Alzheimer’s Association International Conference | Arvinas 2019 July 18; New Haven, Connecticut, United States. Available from:. https://www.globenewswire.com/ news-release/2019/07/18/1884482/0/en/Arvinas-to-Present-Preclinical-Tau-Directed-PROTAC-Protein-Degrader-Data-at-Alzheimer-s-Association-International-Conference.html
[58] 
Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol  2019; 15(10): 937-44.
[http://dx.doi.org/10.1038/s41589-019-0362-y] [PMID: 31527835] 
[59] 
Zhang X, Crowley VM, Wucherpfennig TG, Dix MM, Cravatt BF. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat Chem Biol  2019; 15(7): 737-46.
[http://dx.doi.org/10.1038/s41589-019-0279-5] [PMID: 31209349] 
[60] 
Ottis P, Toure M, Cromm PM, Ko E, Gustafson JL, Crews CM. Assessing different E3 ligases for small molecule induced protein ubiquitination and degradation. ACS Chem Biol  2017; 12(10): 2570-8.
[http://dx.doi.org/10.1021/acschembio.7b00485] [PMID: 28767222] 
[61] 
Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: cargo-specific degraders using selective autophagy. Mol Cell  2019; 76(5): 797-810.
[62] 
Simonetta KR, Taygerly J, Boyle K, et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat Commun  2019; 10(1): 1402.
[http://dx.doi.org/10.1038/s41467-019-09358-9] [PMID: 30926793] 
Rights & Permissions Print Cite
Article Metrics
37
3
DOI https://dx.doi.org/10.2174/2213809907666200130111436	Print ISSN 2213-8099
Publisher Name Bentham Science Publisher	Online ISSN 2213-8102
Technology Transfer and Entrepreneurship (Discontinued)

Targeted Protein Degradation: "The Gold Rush is On!"

Abstract
