Regents of the University of Michigan Ann Arbor United States
Metastatic castration-resistant prostate cancer mCRPC is a lethal disease with about 30,000 estimated annual deaths in U.S, with a vast majority of CRPC driven by androgen receptor AR signaling. AR-signaling is critical for the development and progression of prostate cancer, and AR also the main therapeutic clinical target. AR-targeted therapies, such as AR-antagonists, provide substantial benefits in the treatment of metastatic castration-resistant prostate cancer mCRPC however majority of patients fail these therapies and succumb to the disease. Therefore, there is a clear and pressing need to develop new therapeutics against the AR axis in CRPC. One such novel strategy for targeting the AR-pathway and inhibiting the growth of CRPC has been the use of bromodomain and extraterminal BET protein inhibitors however a new class of molecules that target BET bromodomain proteins through their proteasomal degradation can improve efficacy and specificity. Based on our findings, we hypothesize that pharmacologic BET bromodomain degradation represents an important advance in the treatment CRPC, and may provide a novel therapeutic strategy for advanced prostate cancer. The overall goal of this proposal is to develop very potent small molecule that leads to the proteasomal-degradation of BET bromodomain proteins, with optimized in vivo properties, and to provide a compelling scientific rationale, including detailed mechanistic insight, to facilitate advancement of BET bromodomain degraders asa novel potential therapeutic strategy for patients with the metastatic CRPC.