MON-166 Preclinical characterization of a highly potent and selective HSD17B1 inhibitor for the treatment of endometriosis

Abstract Disclosure: Q. Li: None. G. Shen: None. Z. Hu: None. Y. Xia: None. F. Yang: None. Endometriosis is one of the most prevalent debilitating gynecological disease affecting around 10% women of childbearing age. Albeit a battery of treatment options has been developed, endometriosis remains uncurable so far. Previous reports unveiled that concentrations of 17β-estradiol (E2) were much higher in ectopic lesions than in circulation, and it is believed that an upregulated enzyme named17β-hydroxysteroid dehydrogenase type 1 (HSD17B1), which converts 17β-estrone (E1) to E2, was responsible for the high E2 concentrations in endometriosis lesions. OG6219, an inhibitor of HSD17B1, could dramatically reduce the E2 productions in endometriosis patient tissues. In phase 1 study, OG6219 did not change the reproductive hormone levels comparing to other endometriosis drugs such as GnRH inhibitors. All these studies made HSD17B1 a promising and differentiating targets for treating endometriosis. Herein we disclose the preclinical profiling of a novel HSD17B1 inhibitor GenSci146. GenSci146 potently disrupted HSD17B1 E1 to E2 reductase activity in human recombinant HSD17B1 enzyme, T47D cell lysate and intact cell. GenSci146 failed to disrupt E2 to E1 oxidation in T47D lysate, which hinted that GenSci146 did not inhibit estrogen oxidases. GenSci146 also didn’t show any agonistic or antagonistic effect to ERα or ERβ. Of note, GenSci146 could effectively disrupt E1 to E2 conversion in a set of endometriosis patient derived samples ex vivo. In a human HSD17B1 (hHSD17B1) transgenic mouse model, GenSci146 dose dependently reversed E1 stimulated uterine growth in immature mice, but did not reverse E2 stimulated uterine growth. GenSci146 showed balanced physicochemical properties and favorable pharmacokinetics across several preclinical species. All these data warrants GenSci146 a promising preclinical candidate and the IND filing is expected in early 2026. Presentation: Monday, July 14, 2025