Abstract
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. Invivo, 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.
Highlights
Prostate cancer is a hormone-driven disease that will affect one in nine men (Siegel et al, 2019)
We evaluated these molecules in a mouse mammary tumor virus (MMTV)-driven stable luciferase reporter gene assay in LNCaP cells with a doxycycline-inducible element for exogenous expression of androgen receptor (AR)-V
We demonstrated that KI-ARv03 is a selective cyclin-dependent kinase 9 (CDK9) inhibitor that modulates AR and AR-V7-dependent transcription in vitro
Summary
Prostate cancer is a hormone-driven disease that will affect one in nine men (Siegel et al, 2019). Central to prostate cancer therapeutics is the inhibition of androgen receptor (AR)-driven oncogenic signaling and downstream transcription. AR antagonists such as enzalutamide are potent binders of the ligand-binding domain (LBD) that efficiently block androgen binding and AR activation in prostate cancers (Hoffman-Censits and Kelly, 2013; Tran et al, 2009). Most patients will develop resistance to standard androgen-deprivation therapies (ADTs) and progress to the stage of castration-resistant prostate cancer (CRPC) due to a variety of mechanisms that appear to reactivate the AR pathway (Chandrasekar et al, 2015; Karantanos et al, 2013).
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