Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration Resistant Prostate Cancer


The bromodomain and extraterminal (BET) containing proteins (BRD2/3/4) are essential epigenetic co-regulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off target effects, toxicity, and rapid resistance.


We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient derived xenografts, as well as several techniques including RNA-seq, Mass Spectroscopic Proteomics and Lipidomics.


BET-degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET-inhibitors. We also identified increases in polyunsaturated fatty acids (PUFAs) and Thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.


Compounds inducing the pharmacologic degradation of BET proteins effectively targets the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1250 Enzalutamide (MDV3100) Enzalutamide (MDV3100) is an androgen-receptor (AR) antagonist with IC50 of 36 nM in LNCaP cells. Enzalutamide is shown to increase autophagy. (454) (4)

Related Targets