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

Neeb, A.; Figueiredo, I.; Bogdan, D.; Cato, L.; Strober, J.; Jimenez-Vacas, J. M.; Gourain, V.; Lee, I.; Seeger, R.; Muhle-Goll, C.; Gurel, B.; Welti, J.; Nava-Rodrigues, D.; Rekowski, J.; Qiu, X.; Jiang, Y.; Di Micco, P.; Mateos, B.; Bielskute, S.; Riisnaes, R.; Ferreira, A.; Miranda, S.; Crespo, M.; Buroni, L.; Ning, J.; Brases, S.; Jing, N.; Graessle, S.; Metzger, D.; Swain, A.; Salvatella, X.; Plymate, S.; Al-Lazaikani, B.; LONG, H. W.; Yuan, W.; Brown, M.; Cato, A.; de Bono, J.; Sharp, A.

doi:10.1101/2022.10.17.512378

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bioRxiv · 10.1101/2022.10.17.512378

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

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Abstract

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.

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Neeb, A., Figueiredo, I., Bogdan, D., Cato, L., Strober, J., Jimenez-Vacas, J. M., Gourain, V., Lee, I., Seeger, R., Muhle-Goll, C., Gurel, B., Welti, J., Nava-Rodrigues, D., Rekowski, J., Qiu, X., Jiang, Y., Di Micco, P., Mateos, B., Bielskute, S., Riisnaes, R., Ferreira, A., Miranda, S., Crespo, M., Buroni, L., Ning, J., Brases, S., Jing, N., Graessle, S., Metzger, D., Swain, A., Salvatella, X., Plymate, S., Al-Lazaikani, B., LONG, H. W., Yuan, W., Brown, M., Cato, A., de Bono, J., Sharp, A.. 2022-10-18. Targeting the BAG-1 family of co-chaperones in lethal prostate cancer.. https://doi.org/10.1101/2022.10.17.512378

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