17α-Alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism

Abstract

17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

“…Apoptone, also known as HE3235, is a novel synthetic analogue of 3β‐androstanediol that has shown significant preclinical activity against prostate and breast cancer [65]. In cell lines, apoptone binds to ARs, resulting in the down‐regulation of Bcl‐2 and increased expression of caspases.…”

New Hormonal Therapies for Castration-Resistant Prostate Cancer

“…53, 54 Although its mechanism of activity has not been fully elucidated, HE3235 appears to inhibit conversion of d-cholesterol to d-pregnenolone, without inhibition of CYP17. HE3235 is currently under study in a Phase I/II clinical trial of men with CRPC, with early results demonstrating promising PSA responses.…”

Paradigm Shift in the Concept of Hormonal Milieu of Prostate Cancer

“…Based on the safety and activity observed, the trial continues to accrue an expansion cohort at 100 mg/day of patients with chemotherapy-naive CRPC. [100] 7.8 Inhibitors targeting androgen receptor 7.8.1 A new androgen receptor antagonist, MDV3100 (Fig. 2) As for the conventional anti-androgen, affinity for AR and agonistic activity for AR are matters of concern.…”