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

基本信息

批准号：
9253022
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 30.25万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9253022
关键词：
Address Adverse effects Allosteric Site Area Biological Biological Availability Biological Markers Biology CDK6-associated protein p18 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 Human In Vitro Infertility Knockout Mice Lead Libraries Male Contraceptive Agents Maximum Tolerated Dose Meiosis Methodology Methods Mission Mus National Institute of Child Health and Human Development Natural Products 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 Retinoblastoma Protein Risk Role Safety Side Site Specificity Spermatogenesis Spermatogenic Cell Sterility Structure TP53 gene Testing Testis Therapeutic Toxic effect Vasectomy Work base condoms contraceptive efficacy contraceptive target cross reactivity cyclin A1 design drug development drug discovery drug synthesis experience improved in vivo inhibitor/antagonist innovation kinase inhibitor member men nanomolar novel pill preclinical development public health relevance reversible contraceptive screening small molecule small molecule inhibitor sperm cell success

项目摘要

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）：项目摘要一种可靠、安全且易于使用的可逆非激素男性避孕药将为以下男性提供重要选择：希望在计划生育方面发挥积极作用。目前男性的主要选择是输精管结扎术和避孕套，但两者都分别存在可逆性和手术风险或依从性方面的问题。目前，可逆非激素男性避孕药的药物开发中缺乏药物靶标。蛋白激酶对精子发生过程中的细胞周期进展至关重要，并且可药物化，有望成为避孕药开发的靶点。在这方面，细胞周期蛋白依赖性蛋白激酶2（CDK2）就是这样的一个靶点。 CDK2-/- 敲除小鼠可存活但不育。 CDK2 通过与细胞周期蛋白 A 和 A1 相互作用，靶向视网膜母细胞瘤蛋白 (pRB) 和 p53 进行磷酸化。这两种蛋白质都存在于人类和小鼠睾丸中，在睾丸发育和生精细胞周期转变的调节中发挥着关键作用。因此，有效抑制CDK2的药物应该会阻断精子发生，从而导致因缺乏精子而导致不育。由于CDK2是一种影响减数分裂的酶，一旦不再服用该药物，减数分裂就会恢复，精子的产生也会恢复。这项研究的主要假设是，新型小分子特异性 CDK2 抑制剂可以开发为新型非激素可逆男性避孕药。为了证明这一假设，将实现以下具体目标：具体目标 1. 对可逆抑制大鼠精子发生的已知 CDK2 抑制剂进行鉴定和排序。具体目标 2. 开发新型 CDK2 变构以及 I 型和 II 型激酶抑制剂，以提高 CDK2 特异性、体内抗生精功效并最大限度地减少副作用。具体目标 3. 展示 CDK2 抑制剂的概念验证可逆避孕功效为了实现具体目标，我们将开展两项研究，开发新型 CDK2 抑制剂作为男性避孕药。首先，我们将提高我们最近开发的强效纳摩尔 I 型和 II 型激酶抑制剂的 CDK2 特异性。这种构建特异性的方法以前对我们有用。其次，我们将通过我们最近发现的变构位点开发新型 CDK2 调节剂，因为这可能提供更大的机会获得 CDK2 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。为了成为一种成功且可行的男性避孕药，功效、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，我们预计该项目将生产出新型 CDK2 抑制剂，有望实现安全、有效和简便的目标使用可逆性男性避孕药。