Allosteric CDK2 inhibitor Discovery and Development for Male Contraception

用于男性避孕的变构 CDK2 抑制剂的发现和开发

基本信息

批准号：
10018520
负责人：
Vargheese Mani Chennathukuzhi
金额：
$ 37.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018520
关键词：
Allosteric Site Area Back Binding Binding Sites Bioavailable Biological Assay Biological Markers CCNE1 gene Cardiovascular system Caring Cell Cycle Chemicals Chromosomes Clinical Clinical Trials Complex Contraceptive Agents Contraceptive methods Crystallization Cyclin-Dependent Kinases Cyclins Data Development Drug Design Drug Kinetics Elements Enzyme Inhibition Enzymes Evaluation Exhibits Health Care Costs Human In Vitro Infertility Knockout Mice Lead Libraries Male Contraceptive Agents Medical Meiosis Mitosis Molecular Conformation Mus Occupations Oral Outcome Pharmaceutical Preparations Phase Phosphotransferases Play Pregnancy Production Property Protein Kinase Proteins Research Roentgen Rays Role Series Site Spermatogenesis Sterility Structure Testis Testosterone Therapeutic Woman analog base cancer therapy commercialization cyclin A1 druggable target experience histone H1 kinase in vivo inhibitor/antagonist kinase inhibitor male mouse model nanomolar novel strategies preclinical development prevent scaffold screening segregation side effect small molecule sperm cell unintended pregnancy

项目摘要

PROJECT SUMMARY Testosterone and related analogs have been investigated since the 1960s for male contraception. However, an unfavorable side effect profile, that includes cardiovascular liabilities has prevented commercialization. Therefore, the exploration of non-hormonal targets is considered a novel approach to discover contraceptive agents. Despite this very promising possibility a non-hormonal male contraceptive agent has not entered clinical trial or progressed towards IND-enabling preclinical development. Critical to such an approach is the selection of a validated target. In this regard, cyclin-dependent protein kinase 2 (CDK2) is auspicious because CDK2 knockout mice are healthy but sterile. Our central hypothesis is that we can discover an allosteric CDK2 inhibitor lead and a back-up candidate with a different chemical scaffold in the R61 Phase of this project. Furthermore, we hypothesize that we can develop an allosteric CDK2 inhibitor ready for pre-IND development during the R33 Phase. During the R61 phase we propose to discover an allosteric CDK2 inhibitor series and a back-up series preferably with a different chemical scaffold based on already structurally characterized compounds (x-ray co-crystals) and by additional screening. In an iterative fashion, we will optimize and evaluate analogs of existing and new hits by structure-based drug design. Hits will be optimized by using allosteric site binding assays, CDK2 enzyme inhibition assays, ITC, HSQC NMR, X-ray co-crystal structures, kinase selectivity screens, evaluation of physicochemical properties, in vitro ADMET assays and biomarkers in testis explant mouse model. For the R33 Phase, we plan to develop an allosteric CDK2 inhibitor that is ready for pre-IND development. This lead compound should possess selectivity over other kinases, be orally bioavailable, and exhibit reversible meiotic biomarker expression. A back-up compound preferably from a different chemical series will also be progressed to the in vivo oral proof-of-concept stage. Both objectives will be achieved by continuing compound optimization. Promising compounds will be investigated for complete pharmacokinetic properties, off-target effects, and in vivo proof of concept.

项目概要自 20 世纪 60 年代起，人们就开始研究睾酮及相关类似物用于男性避孕的作用。然而，一个不利的副作用（包括心血管负担）阻碍了商业化。因此，探索非激素目标被认为是发现避孕药具的新方法代理。尽管这种可能性非常有希望，但非激素男性避孕药尚未进入临床试验或取得了支持 IND 的临床前开发的进展。这种方法的关键是选择经过验证的目标。在这方面，细胞周期蛋白依赖性蛋白激酶 2 (CDK2) 是吉祥的，因为 CDK2 敲除小鼠健康但不育。我们的中心假设是我们可以发现变构 CDK2 抑制剂先导物和具有不同化学支架的备用候选物该项目的R61阶段。此外，我们假设我们可以开发出一种变构 CDK2 抑制剂用于 R33 阶段的 IND 前开发。在R61阶段，我们建议最好发现变构CDK2抑制剂系列和备用系列具有基于已结构表征的化合物（X射线共晶）的不同化学支架，并且通过额外的筛选。以迭代的方式，我们将优化和评估现有和新热门的类似产品通过基于结构的药物设计。将通过使用变构位点结合测定、CDK2 酶来优化命中抑制测定、ITC、HSQC NMR、X 射线共晶结构、激酶选择性筛选、评估睾丸外植体小鼠模型中的理化特性、体外 ADMET 测定和生物标志物。对于 R33 阶段，我们计划开发一种变构 CDK2 抑制剂，为 IND 前开发做好准备。这先导化合物应该比其他激酶具有选择性，具有口服生物利用度，并且表现出可逆性减数分裂生物标志物表达。优选来自不同化学系列的备用化合物也将是进展到体内口头概念验证阶段。这两个目标都将通过持续复合来实现优化。将研究有前途的化合物的完整药代动力学特性、脱靶情况效果和体内概念验证。