Identifying primary targets of bumped kinase inhibitor derived compounds to improve utility as therapy for castration resistant prostate cancer

项目总结/文摘

Project Summary/Abstract Castration-resistant prostate cancer (CRPC) that inevitably escapes primary therapies most often retains dependency on androgen receptor (AR). We are repositioning bumped kinase inhibitors (BKIs), originally designed to inhibit Toxoplasma gondii and Cryptosporidium parvum. A class of BKI-derived compounds (BKIDCs) target lethal CRPC by blocking androgen receptor (AR) signaling, placing AR positive CRPC cells in G1 cell cycle arrest to block their proliferation, and inhibiting glycolysis-derived ATP production. Moreover, our safety and pharmacokinetics data indicate that BKIDCs are compounds that can be reasonably developed as a drug for the treatment of CRPC. Importantly, structure–activity relationship studies revealed that BKIDCs appear to exhibit their antiproliferative activities in prostate cancer through off-target effects (not necessarily as kinase inhibitors), which warrants further investigation of their mechanism of action (MOA). In this proposal we will determine the primary sites of BKIDCs’ action in AR-positive prostate cancer cell lines through both hypothesis-driven and unbiased “-Omics” approaches. We will further validate and characterize potential targets by pharmacological and genetic manipulation. By completing the proposed studies, we will learn MOA of BKIDCs and be ready to take further steps to bring BKIDCs to clinic.