Target Engagement

Target Engagement Core Soluble adenylyl cyclase (sAC: ADCY10) is a nonhormonal target, genetically and pharmacologically validated to be essential for male fertility. The goal of this Weill Cornell Medicine Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills which a man would take shortly before sex, only when, and as often as, needed. Using an established, structure- based drug design workflow consisting of (a) modeling and medicinal chemistry; (b) crystallography and structure determination of inhibitor-human sAC complexes; and (c) a battery of in vitro biochemical assays measuring potency, efficacy, and specificity, we successfully developed a series of potent, specific, and drug-like sAC inhibitors suitable for in vivo interrogation of sAC pharmaceutical potential. In preclinical proof-of-concept experiments in mice, a `tool' compound rendered male mice temporarily infertile and identified long residence time on sAC protein as an essential efficacy-defining feature. Thus, we now augment our established workflow with biophysical studies directly assessing binding kinetics. We centralize these biochemical, biophysical, and crystallographic studies examining potency, selectivity, binding kinetics, and molecular interactions of sAC inhibitors into a `closed' technical core. This in vitro Target Engagement core will support all three Projects in the WCM-CRC. While characterization of newly designed analogs in Projects 1 and 3 will constitute its major use, it will also be used to confirm the in vitro efficacy of advanced leads synthesized in larger quantities for the studies in Project 2.