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Sci Adv DOI:10.1126/sciadv.abd6263

Targeting oncoproteins with a positive selection assay for protein degraders.

Publication TypeJournal Article
Year of Publication2021
AuthorsKoduri, V, Duplaquet, L, Lampson, BL, Wang, AC, Sabet, AH, Ishoey, M, Paulk, J, Teng, M, Harris, IS, Endress, JE, Liu, X, Dasilva, E, Paulo, JA, Briggs, KJ, Doench, JG, Ott, CJ, Zhang, T, Donovan, KA, Fischer, ES, Gygi, SP, Gray, NS, Bradner, J, Medin, JA, Buhrlage, SJ, Oser, MG, Kaelin, WG
JournalSci Adv
Volume7
Issue6
Date Published2021 Feb
ISSN2375-2548
Abstract

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.

DOI10.1126/sciadv.abd6263
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33547076?dopt=Abstract

Alternate JournalSci Adv
PubMed ID33547076