Abstract
Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.
Highlights
IntroductionWhile the localized disease can be treated with surgery or radiation therapy, androgen deprivation therapy (ADT) is engaged when cancer spreads
Publisher’s Note: MDPI stays neutralProstate cancer (PCa) remains the most common type of cancer diagnosed in men [1].While the localized disease can be treated with surgery or radiation therapy, androgen deprivation therapy (ADT) is engaged when cancer spreads
We were unable to obtain compounds with significantly improved activities compared to the initial hits [14], we were happy to observe that our design was still selective for cytochrome P450 17A1 (CYP17A1) versus CYP3A4, as indicated by the assay performed on the three most potent compounds (Figure 4B)
Summary
While the localized disease can be treated with surgery or radiation therapy, androgen deprivation therapy (ADT) is engaged when cancer spreads. ADT continues to be the cornerstone of prostate cancer treatment. The disease develops into castration-resistant prostate cancer (CRPC), yielding a poor patient prognosis. Those endeavors introduced the next-generation AR antagonists represented by enzalutamide and apalutamide [2]. The emergence of novel targets such as fatty-acid binding protein 5 (FABP5) [6] illustrates the progress that has been made in the field of prostate cancer. Despite these efforts, PCa still presents a significant problem
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