Cell-cycle regulatory kinases as targets for male contraceptive drug development

细胞周期调节激酶作为男性避孕药物开发的靶点

• 批准号: 8850887
• 负责人: JOSEPH S TASH
• 金额: $ 30.66万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850887
• 关键词: Address; Adverse effects; Allosteric Site; Area; Biological; Biological Availability; Biological Factors; Biological Markers; Biology; Cell Cycle; Cell Cycle Progression; Computer Simulation; Contraceptive Agents; Crystallography; Cyclin A; Cyclin-Dependent Kinases; Cyclins; Data; Development; Digit structure; Drug Design; Drug Kinetics; Enzymes; Family; Family Planning; Female Contraceptive Agents; Fertility; Generations; Goals; Hand; Health; Hormonal; Human; In Vitro; Infertility; Knockout Mice; Lead; Libraries; Male Contraceptions; Male Contraceptive Agents; Maximum Tolerated Dose; Meiosis; Methodology; Methods; Mission; Mus; National Institute of Child Health and Human Development; Operative Surgical Procedures; Oral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Process; Production; Property; Protein Isoforms; Protein Kinase; Proteins; Publishing; Rattus; Recording of previous events; Recovery; Regulation; Research; Research Infrastructure; Research Personnel; Retinoblastoma Protein; Risk; Role; Safety; Site; Specificity; Spermatogenesis; Spermatogenic Cell; Sterility; Structure; Testing; Testis; Therapeutic; Toxic effect; Vasectomy; Work; abstracting; base; condoms; contraceptive efficacy; contraceptive target; cross reactivity; design; drug development; drug discovery; drug synthesis; experience; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; meetings; member; men; novel; pill; pre-clinical; screening; small molecule; sperm cell; success

DESCRIPTION (provided by applicant): Project Abstract A reversible non-hormonal male contraceptive that is reliable, safe, and easy to use will provide a significant option for men who want to take an active role in family planning. The current primary choices for men are vasectomy and condoms, but each has problems with reversibility and surgical risk, or compliance, respective- ly. There is currently a paucity of druggable targets in drug development for reversible non-hormonal male con- traception. Protein kinases that are critical for cell cycle progression during spermatogenesis that are drugga- ble offer promise as targets for contraceptive development. In this regard, cyclin-dependent protein kinase 2 (CDK2) is such a target. CDK2-/- knockout mice are viable but sterile. CDK2 through its interaction with cyclins A and A1 targets retinoblastoma protein (pRB) and p53 for phosphorylation. Both of these proteins are present in human and murine testis, and play critical roles in testis development, and in regulation of transition through the spermatogenic cell cycle. Therefore, a drug that effectively inhibits CDK2 should block spermatogenesis, thereby causing infertility due to lack of sperm. Since CDK2 is an enzyme that effects meiotic division, once the drug is no longer taken, meiosis should resume and sperm production recovers. The primary hypothesis for this research is that novel small molecule specific inhibitors of CDK2 can be developed as novel non-hormonal reversible male contraceptive agents. To prove this hypothe- sis, the following specific aims will be achieved: Specific Aim 1. Identify and rank known inhibitors of CDK2 that reversibly inhibit spermatogenesis in rats. Specific Aim 2. Develop novel CDK2 allosteric and type I and II kinase inhibitors as leads to improve CDK2 specificity, in vivo anti-spermatogenic efficacy, and minimize side effects. Specific Aim 3. Demonstrate proof-of-concept reversible contraceptive efficacy of CDK2 inhibitors To achieve specific aims, we will undertake two lines of research to develop novel CDK2 inhibitors as male contraceptives. First, we will improve the CDK2 specificity for potent nanomolar type I and type II kinase inhibitors that we recently developed. This approach of building in specificity has worked for us before. Second, we will pursue the development of novel CDK2 modulators via an allosteric site that we recently discovered, as these may provide greater opportunities to have CDK2-specific selectivity and minimize cross reactivity with other members of the kinase family. In order to be a successful and viable male contraceptive agent, efficacy, safety, and recovery of fertility will need to be comparable to the oral female contraceptive pill. Based on our experience and success in ongoing contraceptive development projects, one of which is currently in pre-clinical development under FDA guidance, we expect this project to produce novel CDK2 inhibitors with high promise to meet the goal of a safe, effective, and easy to use reversible male contraceptive agent.

描述（由申请人提供）：项目摘要一种可逆的非激素男性避孕药，可靠，安全，易于使用，将为以下男性提供一个重要的选择： 在计划生育中发挥积极作用。目前男性的主要选择是输精管结扎术和避孕套，但每一种都有可逆性和手术风险或依从性的问题。目前在可逆性非激素男性收缩的药物开发中缺乏可药用靶点。在精子发生过程中对细胞周期进程至关重要的蛋白激酶是可药用的，这为避孕药的开发提供了希望。在这方面，细胞周期蛋白依赖性蛋白激酶2（CDK 2）是这样的目标。CDK 2-/-敲除小鼠存活但无菌。CDK 2通过其与细胞周期蛋白A和A1的相互作用靶向视网膜母细胞瘤蛋白（pRB）和p53磷酸化。这两种蛋白质都存在于人类和小鼠睾丸中，并在睾丸发育和生精细胞周期转换的调节中发挥关键作用。因此，有效抑制CDK 2的药物应该会阻断精子发生，从而导致由于缺乏精子而导致不育。由于CDK 2是一种影响减数分裂的酶，一旦不再服用药物，减数分裂应该恢复，精子生产恢复。 本研究的主要假设是，新型小分子特异性CDK 2抑制剂可以开发为新型非激素可逆男性避孕药。为了证明这一假说，将实现以下具体目标：具体目标1。识别和排名已知的CDK 2抑制剂，可逆地抑制大鼠精子发生。 具体目标2。开发新型CDK 2变构和I型和II型激酶抑制剂，以改善CDK 2特异性、体内抗精子生成功效并最大限度地减少副作用。 具体目标3。为了实现特定目标，我们将开展两项研究，以开发新型CDK 2抑制剂作为男性避孕药。首先，我们将提高CDK 2对我们最近开发的有效纳摩尔I型和II型激酶抑制剂的特异性。这种建立特异性的方法以前对我们很有效。其次，我们将通过我们最近发现的变构位点开发新型CDK 2调节剂，因为这些可能提供更大的机会来具有CDK 2特异性选择性，并最大限度地减少与激酶家族其他成员的交叉反应性。为了成为一种成功和可行的男性避孕药，有效性，安全性和生育能力的恢复需要与口服女性避孕药相当。基于我们在正在进行的避孕药开发项目中的经验和成功，其中一个项目目前正在FDA指导下进行临床前开发，我们预计该项目将产生新型CDK 2抑制剂，有望实现安全，有效和易于使用的可逆男性避孕药的目标。