Kinases as Therapeutic Targets for Endometriosis

激酶作为子宫内膜异位症的治疗靶点

基本信息

批准号：
10674987
负责人：
MARTIN M. MATZUK
金额：
$ 68.77万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674987
关键词：
AMHR2 gene Address Affect Affinity BMPR2 gene Bar Codes Binding CSF1R gene Cell Line Cells Cellular biology Chemicals Chemistry Clinical Collection DNA DNA biosynthesis Data Data Set Disease Dysmenorrhea Dyspareunia EPHA2 gene Endocrine Endometrium FDA approved Family Foundations Gene Combinations Gene Expression Genetic Genome Grant Growth Gynecologic Health Hormone Antagonists Hormones Human Genome IRAK3 gene Immunologist In Vitro Incidence Induction of Apoptosis Infertility Infiltration Inflammation Inflammatory Lead Lesion Libraries MAP3K8 gene MYLK gene Mediating Medicine Menorrhagia Metabolic Methods Molecular NTRK2 gene NUAK1 gene National Institute of Child Health and Human Development Organoids Ovarian Clear Cell Tumor Ovarian Endometriosis Pain Paper Pathogenesis Pathologic Pathway interactions Patients Peritoneal Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Physiological Proliferating Promega Protein Kinase Proteins Publishing Recombinants Role Sequential Treatment Small Interfering RNA Stromal Cells Syndrome System TGFBR2 gene Technology Testing Therapeutic Therapeutic Agents Tissues Transforming Growth Factor beta Validation Woman Women&apos s Health Work college comparison control drug discovery drug-like compound efficacious treatment endometrial organoid endometriosis experience in vivo in vivo Model inhibitor interest kinase inhibitor knock-down mouse model multidisciplinary new chemical entity new therapeutic target novel novel therapeutics overexpression patient population pre-clinical public health relevance receptor reproductive screening small molecule small molecule inhibitor technology platform therapeutic target web portal

项目摘要

ABSTRACT The human genome encodes 538 protein kinases, most of which are functionally important and are involved in the pathogenesis of many diseases. This new R01 is a discovery-based grant focused on the molecular validation of novel kinases that are upregulated in endometriosis. To address new therapeutic options for endometriosis, we will validate a subset of endometriosis-implicated kinases using siRNA knockdown strategies and available small molecule inhibitors and subsequently use DNA-Encoded Chemistry Technology (DEC-Tec) to identify novel therapeutic molecules for further chemical validation in vitro and in vivo. We identified dozens of kinases that are statistically upregulated in the lesions of patients with ovarian endometriosis, peritoneal endometriosis, and/or deep infiltrating endometriosis compared to control and patient endometrium. The hypothesis for this R01 is that inhibition of one or more of these novel kinase targets will be effective in the treatment of endometriosis. In this proposal, we outline a comprehensive approach to functionally characterize and target kinases in primary endometriotic stromal cells and organoid cultures derived from women. In parallel, we will utilize state-of-the-art DEC-Tec selection methods available in the Center for Drug Discovery (CDD) at Baylor College of Medicine (BCM) to identify novel kinase inhibitors that will then be re-synthesized without the DNA barcode and chemically optimized by our team. We currently have a screening collection of over 6 billion DNA-encoded molecules. The overarching objective is to identify potent and selective kinase inhibitors that can provide a foundation for new medicines to address the unmet clinical needs of endometriosis patients. The Specific Aims are: 1) Perform target validation of overexpressed kinases; 2) Use DEC-Tec to identify novel small-molecule inhibitors of validated kinases and optimize the selectivity, activity, and stability of high affinity kinase binders; and 3) Evaluate optimized high affinity kinase inhibitors in vitro and in vivo. Identifying new efficacious therapies for endometriosis requires a multifaceted approach that necessitates increased efforts to identify and screen novel targets for drug discovery. Our approach, which combines gene expression datasets for target identification with a novel DEC-Tec drug discovery platform, will rapidly advance key kinase targets through a well-established drug discovery pipeline. Our multidisciplinary team is seeking to discover new chemical entities that address the non-hormonal axes of endometriosis as stand-alone therapy or as sequential therapy during hiatus from endocrine-suppressing agents. Our DEC-Tec platform will help us to find the first specific inhibitors of unexplored kinases (a major druggable class of proteins) that are elevated in endometriosis to dissect these key physiological pathways and pathological mechanisms underlying endometriosis and provide new disease-specific treatment options.

抽象的人类基因组编码 538 种蛋白激酶，其中大部分具有重要功能并参与许多疾病的发病机制。这项新的 R01 是一项基于发现的资助，重点关注分子验证子宫内膜异位症中上调的新型激酶。寻找新的治疗选择子宫内膜异位症，我们将使用 siRNA 敲低验证子宫内膜异位症相关激酶的子集策略和可用的小分子抑制剂，然后使用 DNA 编码化学技术（DEC-Tec）鉴定新型治疗分子，以进行进一步的体外和体内化学验证。我们确定了数十种在卵巢癌患者病变中统计上调的激酶与对照和患者相比，子宫内膜异位症、腹膜子宫内膜异位症和/或深部浸润子宫内膜异位症子宫内膜。该 R01 的假设是，对这些新激酶靶标中的一个或多个的抑制将是对治疗子宫内膜异位症有效。在本提案中，我们概述了一种综合方法对原代子宫内膜异位基质细胞和类器官培养物中的激酶进行功能表征和靶向源自女性。与此同时，我们将利用最先进的 DEC-Tec 选择方法贝勒医学院 (BCM) 药物发现中心 (CDD) 旨在鉴定新型激酶抑制剂然后将在没有 DNA 条形码的情况下重新合成，并由我们的团队进行化学优化。我们目前有超过 60 亿个 DNA 编码分子的筛选集合。总体目标是确定有效的和选择性激酶抑制剂，可以为新药解决未满足的临床问题提供基础子宫内膜异位症患者的需求。具体目标是： 1) 对过度表达的激酶进行靶标验证； 2) 使用 DEC-Tec 鉴定经过验证的激酶的新型小分子抑制剂并优化选择性，高亲和力激酶结合物的活性和稳定性； 3) 评估优化的高亲和力激酶抑制剂体外和体内。确定子宫内膜异位症的新有效疗法需要采取多方面的方法需要加大努力来识别和筛选药物发现的新靶点。我们的方法，将用于目标识别的基因表达数据集与新型 DEC-Tec 药物发现平台相结合，将通过完善的药物发现管道快速推进关键激酶靶标。我们的多学科研究小组正在寻求发现新的化学实体，以解决子宫内膜异位症的非激素轴问题单独治疗或在内分泌抑制剂中断期间作为序贯治疗。我们的 DEC-Tec 该平台将帮助我们找到第一个未开发的激酶（一类主要的可成药药物）的特异性抑制剂蛋白质）在子宫内膜异位症中升高，以剖析这些关键的生理途径和病理途径子宫内膜异位症的潜在机制并提供新的疾病特异性治疗选择。