VT-464

• CAT Number: I002052
• CAS Number: 1610537-15-9
• Molecular Formula: C18H17F4N3O3
• Molecular Weight: 399.34
• Purity: ≥95%
• Target: CYP3A/CYP450
• Solubility: 10 mM in DMSO
• Storage: Store at -20°C
• IC50: 69 nM(h-CYP17 Lyase)
• InChI: InChI=1S/C18H17F4N3O3/c1-9(2)18(26,15-8-23-25-24-15)12-4-3-10-6-13(27-16(19)20)14(28-17(21)22)7-11(10)5-12/h3-9,16-17,26H,1-2H3,(H,23,24,25)/t18-/m0/s1
• InChIKey: ZBRAJOQFSNYJMF-SFHVURJKSA-N
• SMILES: O[C@@](C(C)C)(C1=CC=C2C=C(OC(F)F)C(OC(F)F)=CC2=C1)C3=CN=NN3

VT-464 (CAT: I002052) is a selective androgen receptor degrader (SARD) that acts by targeting the androgen receptor (AR) for degradation. It is being investigated for its potential application in the treatment of castration-resistant prostate cancer (CRPC), which is characterized by the continued activation of the AR signaling pathway despite low levels of circulating androgens. VT-464 has shown promising preclinical results in inhibiting AR activity and inducing tumor regression in CRPC models. By promoting AR degradation, VT-464 aims to disrupt AR signaling and provide a novel therapeutic approach for the management of CRPC. Clinical studies are ongoing to evaluate its safety and efficacy in humans.

Reference

1:Sci Rep. 2016 Oct 17;6:35354. doi: 10.1038/srep35354. Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.Maity SN,Titus MA,Gyftaki R,Wu G,Lu JF,Ramachandran S,Li-Ning-Tapia EM,Logothetis CJ,Araujo JC,Efstathiou E, PMID: 27748439 PMCID: PMC5066251 DOI: 10.1038/srep35354
Abstract: Cytochrome P450 17α-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 17α-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.