Target Engagement

目标参与核心 可溶性腺酰环化酶(SAC：ADCY10)在遗传学和药理学上都是一个非激素靶标 被证实是男性生育所必需的。威尔康奈尔医学避孕研究的目标 中心(WCM-CRC)是将作用强烈的SAC抑制剂开发成按需避孕药，这是一种 男人会在做爱前不久服用，只有在需要的时候才会服用。利用一种既定的结构- 基于药物设计工作流程，包括(A)建模和药物化学；(B)结晶学和 抑制剂-人SAC复合体的结构测定；以及(C)一组体外生化分析 通过测量效力、有效性和特异性，我们成功地开发了一系列有效、特异和 适用于体内SAC药物潜能检测的类药物SAC抑制剂。在临床前阶段 小鼠的概念验证实验，一种“工具”化合物使雄性小鼠暂时不育，并 确定长时间停留在SAC蛋白上是一个基本的疗效定义特征。因此，我们现在 通过直接评估结合动力学的生物物理研究来增强我们已建立的工作流程。我们 集中这些生化、生物物理和结晶学研究，检查效力、选择性、 结合动力学和SAC抑制剂与“封闭”技术核心的分子相互作用。这是一种体外实验 目标参与核心将支持WCM-CRC的所有三个项目。而新的刻画 项目1和项目3中设计的类似物将构成其主要用途，它也将用于确认体外 在项目2的研究中大量合成的先进先导化合物的功效。

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.