Covalent Targeting of Remote Cysteine Residues to Develop CDK12 and CDK13 Inhibitors

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2016 Aug 30

PMID 27571479

Citations 161

Authors

Tinghu Zhang

Nicholas Kwiatkowski

Calla M Olson

Sarah E Dixon-Clarke

Brian J Abraham

Ann K Greifenberg

Scott B Ficarro

Jonathan M Elkins

Yanke Liang

Nancy M Hannett

Theresa Manz

Mingfeng Hao

Bartlomiej Bartkowiak

Arno L Greenleaf

Jarrod A Marto

Matthias Geyer

Alex N Bullock

Richard A Young

Nathanael S Gray

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

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