Discovery and resistance mechanism of a selective CDK12 degrader

Nat Chem Biol. 2021 Jun;17(6):675-683. doi: 10.1038/s41589-021-00765-y.

Baishan Jiang ^# ¹ ², Yang Gao ^# ¹ ², Jianwei Che ^# ¹ ², Wenchao Lu ¹ ², Ines H Kaltheuner ³, Ruben Dries ⁴ ⁵, Marian Kalocsay ⁶, Matthew J Berberich ⁶, Jie Jiang ¹ ², Inchul You ¹ ², Nicholas Kwiatkowski ¹ ², Kristin M Riching ⁷, Danette L Daniels ⁷, Peter K Sorger ⁶, Matthias Geyer ³, Tinghu Zhang ⁸ ⁹, Nathanael S Gray ¹⁰ ¹¹

Affiliations

1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3 Institute of Structural Biology, University of Bonn, Bonn, Germany.
4 Department of Hematology and Oncology, Boston University, Boston, MA, USA.
5 Department of Computational Medicine, Boston University, Boston, MA, USA.
6 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
7 Promega Corporation, Madison, WI, USA.
8 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. tinghu_zhang@dfci.harvard.edu.
9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. tinghu_zhang@dfci.harvard.edu.
10 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
11 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. nathanael_gray@dfci.harvard.edu.
# Contributed equally.

PMID: 33753926 DOI: 10.1038/s41589-021-00765-y

Abstract

Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and Other transcriptional CDKs, most notably CDK13. In the present study, we report the rational design and characterization of a CDK12-specific degrader, BSJ-4-116. BSJ-4-116 selectively degraded CDK12 as assessed through quantitative proteomics. Selective degradation of CDK12 resulted in premature cleavage and poly(adenylation) of DDR genes. Moreover, BSJ-4-116 exhibited potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor olaparib, as well as when used as a single agent against cell lines resistant to covalent CDK12 inhibitors. Two point mutations in CDK12 were identified that confer resistance to BSJ-4-116, demonstrating a potential mechanism that tumor cells can use to evade bivalent degrader molecules.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-139039

BSJ-4-116

98.73%, PROTAC CDK12 Degrader

PROTACs; CDK

Cancer

Name
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