Targeting the BAG-1 family of co-chaperones in lethal prostate cancer

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC. ### Competing Interest Statement L.C. is now an employee of Sanofi. M.B. is a consultant to and receives sponsored research support from Novartis. B.A-L. is an employee of MD Anderson Cancer Center which operates a Reward to Inventors Scheme. B.A-L. declares commercial interest in Exscientia and AstraZeneca. B.A-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, Astellas Pharma and is an ex-employee of Inpharmatica Ltd. M.B. serves on the Scientific Advisory Board of Kronos Bio, H3 Biomedicine and GV20 Oncotherapy. J.S.d.B. has served on advisory boards and received fees from many companies, including Amgen, Astra Zeneca, Bayer, Bioxcel Therapeutics, Cellcentric, Daiichi, Eisai, Genentech/Roche, GSK, Harpoon, ImCheck Therapeutics, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Pfizer, and Sanofi Aventis. He is an employee of the ICR, which has received funding or other support for his research work from AstraZeneca, Astellas, Bayer, CellCentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income). J.S.d.B. was named as an inventor, with no financial interest, for patent 8,822,438, submitted by Janssen, that covers the use of abiraterone acetate with corticosteroids. J.S.d.B. has been the CI/PI of many industry-sponsored clinical trials. A.Sharp is an employee of the ICR, which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income). A. Sharp has received travel support from Sanofi, Roche-Genentech and Nurix, and speaker honoraria from Astellas Pharma and Merck Sharp & Dohme. He has served as an advisor to DE Shaw Research and CHARM Therapeutics. A. Sharp has been the CI/PI of industry-sponsored clinical trials. The remaining authors declare no conflicts of interest.