@article{3cd037d0f66e48e2b3398b0fca50946d,
title = "Exploring Targeted Degradation Strategy for Oncogenic KRASG12C ",
abstract = "KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRASG12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/KRASG12C dimerization, and degraded GFP-KRASG12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRASG12C. KRASG12C is an oncoprotein of high interest for drug development. Zeng et al. investigate targeting KRASG12C for degradation using small-molecule degraders (PROTACs) and document challenges and opportunities in this area.",
keywords = "CRBN, KRAS, PROTAC, caner, degrader, targeted protein degradation, ubiquitination",
author = "Mei Zeng and Yuan Xiong and Nozhat Safaee and Nowak, {Rados{\l}aw P.} and Donovan, {Katherine A.} and Yuan, {Christine J.} and Behnam Nabet and Gero, {Thomas W.} and Frederic Feru and Lianbo Li and Sudershan Gondi and Ombelets, {Lincoln J.} and Chunshan Quan and J{\"a}nne, {Pasi A.} and Milka Kostic and Scott, {David A.} and Westover, {Kenneth D.} and Fischer, {Eric S.} and Gray, {Nathanael S.}",
note = "Funding Information: We thank Dr. Eric Wang for his critical reading of the manuscript. The Gray lab gratefully acknowledges funding from Katherine and Steve Pinard (to B.N. and N.S.G.), the Hale Center for Pancreatic Cancer (to N.S.G.), and Astellas Pharmaceuticals (to N.S.G.). The Fischer lab gratefully acknowledges funding from Astellas Pharmaceuticals (to E.S.F.). E.S.F. is a Damon Runyon-Rachleff Innovator supported in part by the Damon Runyon Cancer Research Foundation ( DRR-50–18 ). This study was also supported by grants CPRIT RP170373 (to K.D.W.), DOD W81XWH-15-LCRP-IDA (to K.D.W.), American Cancer Society Postdoctoral Fellowship PF-17-010-01-CDD (to B.N.), and Stand Up To Cancer -American Cancer Society Lung Cancer Dream Team Translational Research Grant (to P.A.J.) (grant no. SU2C-AACR-DT17-15 ). Stand Up To Cancer is a program of the Entertainment Industry Foundation . Research grants are administered by the American Association for Cancer Research , the scientific partner of SU2C. Funding Information: We thank Dr. Eric Wang for his critical reading of the manuscript. The Gray lab gratefully acknowledges funding from Katherine and Steve Pinard (to B.N. and N.S.G.), the Hale Center for Pancreatic Cancer (to N.S.G.), and Astellas Pharmaceuticals (to N.S.G.). The Fischer lab gratefully acknowledges funding from Astellas Pharmaceuticals (to E.S.F.). E.S.F. is a Damon Runyon-Rachleff Innovator supported in part by the Damon Runyon Cancer Research Foundation (DRR-50–18). This study was also supported by grants CPRIT RP170373 (to K.D.W.), DOD W81XWH-15-LCRP-IDA (to K.D.W.), American Cancer Society Postdoctoral Fellowship PF-17-010-01-CDD (to B.N.), and Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (to P.A.J.) (grant no. SU2C-AACR-DT17-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. N.S.G. E.S.F. D.A.S. N.S. Y.X. M.Z. and R.P.N. designed the research. N.S. Y.X. M.Z. R.P.N. K.A.D. T.W.G. F.F. C.J.Y. L.L. L.J.O. S.G. and C.Q. performed the experiments. Y.X. T.W.G. F.F. and D.A.S. designed and synthesized the compounds. M.Z. N.S. Y.X. D.A.S. K.A.D. R.P.N. C.J.Y. L.L. and B.N. analyzed and interpreted the data. N.S.G. E.S.F. D.A.S. K.D.W. P.A.J. and R.P.N. provided administrative, technical, or material support. M.Z. Y.X. N.S. M.K. D.A.S. E.S.F. and N.S.G. wrote the manuscript. N.S.G. is a founder, science advisory board member and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. E.S.F. is a founder and/or member of the scientific advisory board, and equity holder of C4 Therapeutics and Civetta Therapeutics and a consultant to Novartis, AbbVie, and Pfizer. The Fischer lab receives research funding from Novartis, Deerfield, and Astellas. K.D.W. is a scientific advisory board member of Vibliome Therapeutics. P.A.J. reports receiving commercial research grants from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Astellas Pharmaceuticals, Eli Lilly, Takeda Oncology, and PUMA; holds ownership interest (including patents) in Gatekeeper Pharmaceuticals and LOXO Oncology; is a consultant/advisory board member for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai, Ariad, Ignyta, LOXO Oncology, SFJ Pharmaceuticals, Voronoi, Takeda Oncology, Daiichi Sankyo, Novartis, Eli-Lilly Biocartis, and Mirati Therapeutics; and receives post-marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp. Funding Information: E.S.F. is a founder and/or member of the scientific advisory board, and equity holder of C4 Therapeutics and Civetta Therapeutics and a consultant to Novartis, AbbVie, and Pfizer. The Fischer lab receives research funding from Novartis, Deerfield, and Astellas. K.D.W. is a scientific advisory board member of Vibliome Therapeutics. P.A.J. reports receiving commercial research grants from AstraZeneca , Boehringer Ingelheim , Daiichi-Sankyo , Astellas Pharmaceuticals, Eli Lilly , Takeda Oncology , and PUMA ; holds ownership interest (including patents) in Gatekeeper Pharmaceuticals and LOXO Oncology; is a consultant/advisory board member for AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai, Ariad, Ignyta, LOXO Oncology, SFJ Pharmaceuticals, Voronoi, Takeda Oncology, Daiichi Sankyo, Novartis, Eli-Lilly Biocartis, and Mirati Therapeutics; and receives post-marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2020",
month = jan,
day = "16",
doi = "10.1016/j.chembiol.2019.12.006",
language = "English (US)",
volume = "27",
pages = "19--31.e6",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "1",
}