Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors

Abstract

The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently inhibits both reactions catalyzed by CYP17, the 17α-hydroxylase (hydroxylase) reaction as well as the 17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome (MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less avid, metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6 (VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

“…The data were subjected to exponential growth-curve analysis constrained to share an initial value and to 2-way ANOVA analysis followed by Bonferroni's multiple comparisons test. Significant differences as compared with the vehicle-treated control group (P < 0.05) were detected only for seviteronel at a dose of 100 mg/kg (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28].…”

“…Seviteronel and galeterone emerged from programs whose goals were to develop inhibitors that did not impact the hydroxylase activity of the enzyme, thus negating the need for cortisol replacement (16,18). In agreement with preclinical data showing minimal effects on CYP17 hydroxylase function, the initial phase I and II studies of seviteronel for CRPC have been conducted without supplemental steroids, indicating that it is possible to block adrenal androgen production without negatively impacting glucocorticoid production (51).…”

“…However, seviteronel was found to be as effective as enzalutamide in preventing androgen-mediated target gene expression ( Figure 1E), while galeterone and abiraterone were less effective on a subset of AR target genes (e.g., N-Myc downstream-regulated 1 [NDRG1], diazepam-binding inhibitor, acyl-CoA-binding protein [DBI], and hydroxyprostaglandin dehydrogenase [HPGD]), likely reflecting their lower binding affinity for the T877A mutation. Individual graphs for the kallikrein-related peptive inhibition of CYP17 lyase activity could negate the need for concomitant administration of glucocorticoids by sparing CYP17 hydroxylase activity (16)(17)(18).…”

Anticancer Activity of a Novel Selective CYP17A1 Inhibitor in Preclinical Models of Castrate-Resistant Prostate Cancer

“…AA (MedChem Express) was used for in vivo evaluations. VT-464 design and synthesis have been described elsewhere (9).…”

Enantioselective endocrine disrupting effects of omeprazole studied in the H295R cell assay and by molecular modeling

“…Thus, the DFT study confirms the weak interactions to the Fe ion suggested by the docking. Interestingly, weak binding to the heme group have previously been associated with lyase inhibition, like OME in this study (Rafferty et al, 2014).…”