BET Bromodomain Degraders for the Treatment of Metastatic Prostate Cancer

Posted February 21, 2020

Steven Kregel, Ph.D., University of Michigan

 Michael Yu, Ph.D.; University of Utah
Dr. Steven Kregel,
University of Michigan

The standard treatment for advanced, metastatic prostate cancer (PCa) involves blocking the body’s production of androgens by targeting the androgen receptor (AR), which drives the growth of PCa cells. While this treatment option is initially successful, most acquire resistance and ultimately progress to lethal disease. Consequently, there is a critical need to develop drugs targeting other proteins involved in AR activity rather than AR directly. One protein group that represents a good therapeutic target is called bromodomain and extraterminal (BET) containing proteins, which interact with AR to drive PCa progression to metastatic disease. There have been great efforts to target BET proteins by blocking the action of these proteins, although many of these drugs are not specific, have off target side effects, and often lead to rapid drug resistance. Dr. Steven Kregel and his research team at the University of Michigan have aimed to develop molecules that target BET proteins through a different mechanism, called proteosomal degradation, in which the compound tags the BET protein for the body’s own recycling.

With funding from a PCRP FY16 Early Investigator Research Award and under the mentorship of Dr. Arul Chinnaiyan, Dr. Kregel has tested and characterized several candidate inhibitors in preclinical PCa models. Through this work, he has identified the BET degrader, dBET-3 (ZBC-260), as the lead candidate compound. He first tested this compound in a panel of PCa cell lines and found that it effectively degraded BET proteins as well as another cancer-driving gene called MYC. Through patient-derived tumor mouse models, he discovered that mice treated with dBET-3 had significantly smaller, slower-growing tumors than the control group. Importantly, the BET degrader was effective at inhibiting PCa growth at lower concentrations than BET inhibitors both in vitro and in vivo.

This research group is continuing to test the dBET-3 compound in preclinical models of drug-tolerability and dosage in preparation for a phase 1 clinical trial in prostate cancer patients. Additional versions of the drug to improve its bioavailability and cancer cell-specific targeting are also being developed, such as the newly characterized QCA570, as well as selective inhibitors of individual BET proteins to prevent potential tissue-specific side effects. This group now has multiple modifications of the lead compound, dBET-3, being produced for phase 1 clinical trials. Ultimately, they hope to advance this work into the clinic for the treatment of metastatic prostate cancer. 

Micahel Yu Figure

Schematic of BET-degrader targeting BRD4 though poly-ubiquitin conjugation and subsequent degradation by the proteasome complex.


Kregel S, Malik R, Asangani IA, Wilder-Romans K, Rajendiran T, Xiao L, Vo JN, Soni T, Cieslik M, Fernadez-Salas E, Zhou B, Cao X, Speers C, Wang S, Chinnaiyan AM. Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer. Clin Cancer Res. 2019 Mar 27. doi: 10.1158/1078-0432.CCR-18-3776. PubMed PMID: 30918020

Qin C, Hu Y, Zhou B, Fernandez-Salas E, Yang CY, Liu L, McEachern D, Pryzbranowski S, Wang M, Stuckey J, Meagher J, Bai L, Chen Z, Lin M, Yang J, Xu F, Hu J, Xing W, Huang L, Li S, Wen B, Sun D, Wang S. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. J Med Chem. 2018 Aug 9. doi: 10.1021/acs.jmedchem.8b00506 PubMed PMID: 30019901


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

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Last updated Thursday, May 26, 2022