New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

In our effort to find small-molecule
treatments of advanced prostate
cancers (PCs), a 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 submicromolar 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. 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 are discussed.