Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
Name
1-s2.0-S2451945620303809-main.pdf
Description
Published version
Size
4.14 MB
Format
Unknown
Checksum (MD5)
cdd24c7be79afd32f82d5ad2b204abb8
Author(s)
Richters, André
Doyle, Shelby K.
Freeman, David B.
Lee, Christina
Leifer, Becky S.
Jagannathan, Sajjeev
Kabinger, Florian
Koren, Jošt Vrabič
Struntz, Nicholas B.
Urgiles, Julie
Date Issued
February 2021
Journal
Cell Chemical Biology
Publisher
Elsevier BV
Version
Final published version
Abstract
© 2020 The Authors Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC. In the pursuit of hormone receptor modulators in prostate cancer, a potent, ultraselective CDK9 inhibitor is discovered. This study describes the most selective inhibitors of CDK9 known to date and provides compelling preclinical in vitro and in vivo support for CDK9 as a therapeutic target.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Center for Precision Cancer Medicine
Massachusetts Institute of Technology. Department of Biological Engineering
Harvard University--MIT Division of Health Sciences and Technology
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.chembiol.2020.10.001
