Discovery and Structure-Based Optimization of Novel Atg4B Inhibitors for the Treatment of Castration-Resistant Prostate Cancer

Autophagy inhibition is an attractive
target for cancer therapy.
In this study, we discovered inhibitors of Atg4B essential for autophagosome
formation and evaluated their potential as therapeutics for prostate
cancer. Seventeen compounds were identified as candidates after in silico screening and a thermal shift assay. Among them,
compound 17 showed the most potent Atg4B inhibitory activity,
inhibited autophagy induced by anti-castration-resistant prostate
cancer (CRPC) drugs, and significantly enhanced apoptosis. Although 17 has been known as a phospholipase A2 (PLA2) inhibitor, other PLA2 inhibitors had no effect
on Atg4B and autophagy. We then performed structural optimization
based on molecular modeling and succeeded in developing 21f (by shortening the alkyl chain of 17), which was a
potent competitive inhibitor for Atg4B (Ki = 3.1 μM) with declining PLA2 inhibitory potency.
Compound 21f enhanced the anticancer activity of anti-CRPC
drugs via autophagy inhibition. These findings suggest
that 21f can be used as an adjuvant drug for therapy
with anti-CRPC drugs.