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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：
8727232
负责人：
JOSEPH S TASH
金额：
$ 23.55万
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/8727232
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 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 public health relevance screening small molecule 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.

项目摘要：一种可靠、安全、易于使用的可逆非激素男性避孕药将为男性提供一个重要的选择