Targeting soluble adenylyl cyclase for on-demand contraception

Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily ancient, intracellular source of cAMP that is molecularly and mechanistically distinct from the more widely studied, hormone-responsive, G protein regulated transmembrane adenylyl cyclases. Unlike other mammalian cyclases, sAC is most abundantly expressed in male germ cells and is directly regulated by bicarbonate and calcium. Genetic and pharmacological evidence in rodents and humans establishes sAC as essential for male fertility: loss of sAC activity yields immotile sperm incapable of fertilizing the egg resulting in male-specific infertility. These features position sAC as a promising target for developing nonhormonal, on-demand contraceptives suitable for men and women. A proof-of-concept inhibitor has demonstrated a rapid, reversible contraceptive effect <i>in vivo</i> in mice, but translation to a clinical product must address challenges inherent to on-demand sperm-targeted pharmacology. In addition to ensuring a high safety margin and navigating an emerging regulatory and commercial landscape, common to any male contraceptive, on-demand male contraception must define onset/duration of efficacy while ensuring persistent inactivation of sperm function after ejaculation.