VT-464

VT-464 is a reversible, uncompetitive inhibitor of human CYP17 lyase with an IC50 value of 69nM, and also a competitive inhibitor of hydroxylase with an IC50i value of 670nM [1].

VT-464 is a reversible, uncompetitive inhibitor of CYP17 which is is a single protein with two distinct enzyme activities, 17 α-hydroxylase (hydroxylase) and 17, 20-lyase (lyase). Thus VT-464 has shown a reversible, uncompetitive inhibition of CYP17 lyase with a Ki value of 84nM, and a competitive inhibition of hydroxylase with a Ki value of 620nM. In addition, VT-464 has been reported to significantly inhibit to AR transactivation and AR-dependent PSA and NKX3.1 gene transcription in C4-2, C4-2B, MR49C and MR49F cells [1, 2].

References:
[1] Pisle S T, Pressler H M, Troutman S M, et al. Activity of VT-464, a selective CYP17 lyase inhibitor, in the LNCaP prostate cancer xenograft model[C]//JOURNAL OF CLINICAL ONCOLOGY. 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA: AMER SOC CLINICAL ONCOLOGY, 2012, 30(5).
[2] Eisner J R, Abbott D H, Bird I M, et al. VT-464: a novel, selective inhibitor of P450c17 (CYP17)-17, 20 lyase for castration-refractory prostate cancer (CRPC)[C]//JOURNAL OF CLINICAL ONCOLOGY. 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA: AMER SOC CLINICAL ONCOLOGY, 2012, 30(15).

Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.[Pubmed:27748439]

Sci Rep. 2016 Oct 17;6:35354.

Cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17alpha-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status.

Seviteronel (VT-464) is a potent CYP17 lyase inhibitor(h-Lyase IC50=69 nM) that demonstrated both exceptional in vitro lyase/hydroxylase selectivity (~10-fold) and oral activity in a hamster model of androgen biosynthesis inhibition.

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