The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer

by Selleckchem | Aug 22 2023

Background: Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.

Methods: The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.

Results: CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.

Conclusions: This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds.

Comments:

Summary: The study aimed to investigate the effectiveness of CT7001, an orally bioavailable cyclin-dependent kinase 7 (CDK7) inhibitor, in castration-resistant prostate cancer (CRPC). The researchers examined the antitumor activity of CT7001 in vitro using CRPC models and in vivo using xenograft models. They also explored the mechanisms underlying CT7001's activity alone and in combination with the antiandrogen enzalutamide.

The results showed that CT7001 selectively targeted CDK7 in prostate cancer cells, leading to the inhibition of cell proliferation and cell cycle arrest. It also activated p53, induced apoptosis, and suppressed transcription mediated by full-length and constitutively active androgen receptor (AR) splice variants, contributing to its antitumor efficacy in vitro. In xenograft models, oral administration of CT7001 inhibited the growth of CRPC tumors and significantly enhanced the growth inhibition achieved by enzalutamide. Transcriptomic analyses of treated xenografts suggested that CT7001 exerted its effects in vivo by inhibiting cell cycle progression and AR signaling.

Based on these findings, the study supports CDK7 inhibition as a therapeutic strategy for targeting dysregulated cell proliferation in CRPC. CT7001 emerged as a promising candidate for CRPC treatment, either as a standalone therapy or in combination with AR-targeting compounds like enzalutamide.