Targeting oncoproteins with a positive selection assay for protein degraders

Sci Adv. 2021 Feb 5;7(6):eabd6263. doi: 10.1126/sciadv.abd6263.

Vidyasagar Koduri ¹, Leslie Duplaquet ¹, Benjamin L Lampson ¹, Adam C Wang ¹, Amin H Sabet ¹, Mette Ishoey ¹, Joshiawa Paulk ¹, Mingxing Teng ² ³, Isaac S Harris ⁴ ⁵, Jennifer E Endress ⁴ ⁵, Xiaoxi Liu ² ⁶, Ethan Dasilva ² ⁶, Joao A Paulo ⁵, Kimberly J Briggs ¹, John G Doench ⁷, Christopher J Ott ¹, Tinghu Zhang ² ³, Katherine A Donovan ² ³, Eric S Fischer ² ³, Steven P Gygi ⁵, Nathanael S Gray ² ³, James Bradner ⁸, Jeffrey A Medin ⁹, Sara J Buhrlage ² ⁶, Matthew G Oser ¹⁰ ¹¹ ¹², William G Kaelin Jr ¹⁰ ¹² ¹³

Affiliations

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
4 Ludwig Cancer Center, Boston, MA 02115, USA.
5 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
6 Linde Program in Chemical Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
8 Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
9 Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. [email protected] [email protected].
11 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
12 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
13 Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

PMID: 33547076 DOI: 10.1126/sciadv.abd6263

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-155218

TMX-2172

99.38%, CDK2/CDK5 PROTAC Degrader

PROTACs; CDK

Cancer

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