Dual-action small-molecule VSP-51-2 ameliorates polycystic ovary syndrome via PPARγ modulation and AKR1C3 inhibition.

Abstract

Polycystic ovary syndrome (PCOS), a prevalent multifactorial endocrine disorder, is inadequately managed by current therapies that fail to concurrently target its core metabolic (insulin resistance) and reproductive (hyperandrogenism) pathologies. We report VSP-51-2, a dual-target lead compound initially engineered as a selective PPARγ modulator that unexpectedly exerts potent uncompetitive inhibition of the androgen-synthesizing enzyme AKR1C3 through a putative allosteric mechanism. In preclinical PCOS models, VSP-51-2 restored regular estrous cyclicity, improved ovarian follicular morphology, enhanced systemic insulin sensitivity, suppressed hyperandrogenism, and did not significantly perturb measured hypothalamic-pituitary-ovarian (HPO) axis hormonal parameters. Mechanistically, it blocks PPARγ phosphorylation at Ser273, thereby enhancing adiponectin secretion and GLUT4-mediated glucose uptake, and is predicted to bind a putative allosteric pocket of AKR1C3 to constrain androgen biosynthesis. These findings support VSP-51-2 as a preclinical proof-of-concept compound for a dual-target strategy that addresses metabolic dysfunction and androgen excess through a unified molecular scaffold.

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