Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer

A series of propanamide derivatives were designed, synthesized,
and pharmacologically characterized as selective androgen receptor
degraders (SARDs) and pan-antagonists that exert a broad-scope androgen
receptor (AR) antagonism. Incorporating different basic heteromonocyclic
B-ring structural elements in the common A-ring–linkage–B-ring
nonsteroidal antiandrogen general pharmacophore contributed to a novel
scaffold of small molecules with SARD and pan-antagonist activities
even compared to our recently published AF-1 binding SARDs such as
UT-69 (11), UT-155 (12), and UT-34 (13). Compound 26f exhibited inhibitory and degradation
effects in vitro in a wide array of wtAR, point mutant, and truncation
mutant-driven prostate cancers (PCs). Further, 26f inhibited
tumor cell growth in a xenograft model composed of enzalutamide-resistant
(EnzR) LNCaP cells. These results demonstrate an advancement toward
the development of novel SARDs and pan-antagonists with efficacy against
EnzR prostate cancers.