In our effort to find small molecule treatments of advanced prostate cancers (PCs), the novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced sub-micromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells, and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Disclosed is the design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration resistant, Enz-R, and/or AR SV dependent advanced PCs that are often untreatable with known hormone therapies.
Bibliographical noteThis research was supported by the Van Vleet Endowed Professorship (D.D.M.), and GTx, Inc. grant (R.N. and D.D.M.) We thank GTx, Inc. for supporting this project and Dr. Dejian Ma of UTHSC, College of Pharmacy for assistance with 2D NMR and HRMS experiments.
- structure-activity relationship
- selective androgen receptor degrader
- androgen receptor
- androgen receptor splice variant
- AR escape mutants
- prostate cancer
- Antiandrogen resistance
- Enzalutamide resistance
- Castration-resistant prostate cancer
- N-terminal domain
- Ligand binding domain
- Prostate-specific antigen
- AR activation function domain-1