Development AMHR2 agonists as ovarian modulators and contraceptives

About This Grant

Project Summary/Abstract: Current hormonal contraceptives work by disrupting the hypothalamic-pituitary-gonadal axis and preventing follicle development only in its last stage leading to ovulation. All current hormonal contraceptives share unwanted side effects due to the wide tissue distribution of sex steroid receptors. In contrast, anti-Müllerian hormone (AMH) functions by inhibiting the earliest steps of primordial follicle activation and early pre-antral follicle growth, which are gonadotropin-independent. Furthermore, AMH receptor (AMHR2) expression is highly restricted to reproductive organs. Our preliminary data has validated AMHR2 as a contraceptive target by demonstrating that recombinant AMH can rapidly and reversibly induce long-term contraception in multiple mammalian models, with no overt toxicity, and no significant loss of sex steroid production. However recombinant AMH protein and gene therapy treatments are currently impractical and not cost-effective for long-term human contraception. We therefore propose to develop a novel class of female contraceptives that target AMHR2 and work by inhibiting pre-antral follicles. Our long-term goal is to identify a lead candidate AMHR2 agonist that is safe and effective at producing contraception in preclinical models and could be translated to a clinical trial in women. In Aim 1 we will investigate the druggability of AMHR2, and the mechanism of action of small molecule agonists. We will also develop new in silico models and cell-free in vitro binding assays based on binding to the kinase domain of AMHR2 and induction of type I receptors. In Aim 2 we will design and evaluate analogs of CYC116, a hit identified in previous, screening efforts, using an iterative approach to enhance potency, and specificity. Biological activity of CYC116 analogs will be confirmed using ex vivo cultures of mouse ovaries and rat fetal urogenital ridges. In Aim 3 we will perform in vivo preclinical evaluation of CYC116, and other lead candidate agonists, to determine their pharmacokinetics, pharmacodynamics, and toxicity. AMHR2 agonists will be evaluated in mating studies in mice to evaluate their effectiveness at producing contraception, effects on the reproductive system, reversibility, and teratogenicity. We expect these studies to demonstrate whether small molecules that agonize AMHR2 have a potential utility as non-hormonal female contraceptives.