A Pipeline to Screen and Validate MISR2 Agonists as Contraceptives that Inhibit Primordial Follicles

Patricia Donahoe and David Pepin of Massachusetts General Hospital in the U.S. are using a cell-based screening platform to develop a new class of hormonal contraceptive that works at the early stage of primordial follicle activation to prolong the contraceptive effect and reduce side effects, thereby promoting wider use particularly in the developing world. This early stage of follicle development in the ovary is suppressed by a hormone (Mullerian inhibiting substance or MIS) to regulate egg production. They considered that a drug that could mimic MIS could completely suppress ovulation and act as a powerful contraceptive. In contrast, most available hormonal contraceptives work once ovulation has begun, thereby requiring daily dosage, and share unwanted side effects including migraine and increased risk of some diseases. In Phase I, they designed a luciferase-based screening platform using engineered mammalian cells and screened 5,500 compounds from which they validated three candidate contraceptive compounds with high specificity and activity and limited toxicity. In Phase II, they will adapt their assay for higher throughput screening and screen 100,000 compounds to identify diverse classes of molecules for evaluation as ovarian suppressants. The contraceptive efficacy of validated candidates with favorable properties will then be tested in mice.