Target Engagement

目标参与度

• 批准号: 10747155
• 负责人: LONNY R LEVIN
• 金额: $ 25.46万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747155
• 关键词: Acute; Adenylate Cyclase; Antiviral Agents; Binding; Biochemical; Biochemistry; Biological Assay; Biophysics; Cell Line; Cellular Assay; Characteristics; Chemicals; Complex; Computer Models; Contraceptive Agents; Contraceptive methods; Crystallography; Cyclic AMP; Darkness; Deposition; Development; Devices; Dose; Drug Design; Drug Kinetics; Ejaculation; Elements; Engineering; Environment; Enzymes; Female; GTP-Binding Proteins; Goals; Guanylate Cyclase; Human; In Vitro; Individual; Infertility; Kinetics; Laboratories; Lead; Light; Male Contraceptive Agents; Measures; Medicine; Membrane; Modeling; Molecular Conformation; Mus; Oral Contraceptives; Oranges; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiology; Printing; Property; Proteins; Protocols documentation; Publications; Reproducibility; Research; Resolution; Seminal fluid; Series; Specificity; Structure; Surface Plasmon Resonance; Testing; Time; Topical application; Toxic effect; USAID; Update; Vaginal Ring; Woman; Work; X-Ray Crystallography; analog; biophysical analysis; chemical synthesis; contraceptive efficacy; design; drug development; efficacy evaluation; experimental study; improved; in vivo; inhibitor; lead optimization; male; male fertility; man; novel; pharmacologic; pre-clinical; rational design; reproductive tract; residence; scaffold; scale up; sex; sperm cell; structural biology; tool; uptake

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.

目标参与核心 可溶性腺苷酸环化酶（sAC：ADCY10）在遗传和药理学上是一种非激素靶标 经证实对男性生育能力至关重要。威尔康奈尔医学避孕研究的目标 中心 (WCM-CRC) 致力于将具有急性作用的 sAC 抑制剂开发成按需避孕药， 男人会在性行为前不久服用，仅在需要时服用。使用既定的结构 基于药物设计的工作流程，包括 (a) 建模和药物化学； (b) 晶体学和 抑制剂-人sAC复合物的结构测定； (c) 一系列体外生化测定 通过测量效力、功效和特异性，我们成功开发了一系列有效的、特异性的和 类药 sAC 抑制剂，适用于体内研究 sAC 的药学潜力。在临床前 在老鼠身上进行的概念验证实验，一种“工具”化合物使雄性老鼠暂时不育 将 sAC 蛋白上的长停留时间确定为一个重要的功效定义特征。因此，我们现在 通过直接评估结合动力学的生物物理学研究来增强我们既定的工作流程。我们 集中这些生物化学、生物物理和晶体学研究，检查效力、选择性、 sAC 抑制剂的结合动力学和分子相互作用成为“封闭”的技术核心。这在体外 Target Engagement 核心将支持 WCM-CRC 中的所有三个项目。在表征新 项目1和项目3中设计的类似物将构成其主要用途，也将用于确认体外 为项目 2 的研究大量合成的先进先导化合物的功效。