LAUSR

Significance This study aims to identify drugs that activate the Mullerian inhibiting substance pathway to be used for contraception or other applications in women’s health. We describe a high-throughput screening pipeline to identify small molecules that activate the Mullerian inhibiting substance type 2 receptor (MISR2) and validate their activity in bioassays. We identify five compounds from a repurposed drug library that specifically induce MISR2 signaling, trigger regression of the Mullerian duct, and inhibit follicle activation. We test these compounds in vivo and show that they can repress folliculogenesis in mice and rats in an Misr2-dependent manner. These drugs may represent a class of ovarian regulators that inhibit preantral follicle activation and growth.