Kinases as Therapeutic Targets for Endometriosis

激酶作为子宫内膜异位症的治疗靶点

• 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
• 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' 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

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.

摘要 人类基因组编码538种蛋白激酶，其中大多数在功能上是重要的，并参与 许多疾病的发病机制。这个新的R 01是一个以发现为基础的赠款，专注于分子 子宫内膜异位症中上调的新型激酶的确认。为了解决新的治疗选择， 在子宫内膜异位症中，我们将使用siRNA敲低来验证与子宫内膜异位症相关的激酶的子集 策略和可用的小分子抑制剂，并随后使用DNA编码化学技术 （DEC-Tec）以鉴定新型治疗分子，用于体外和体内的进一步化学验证。我们 他们发现了几十种在卵巢癌患者病变中统计学上上调的激酶， 子宫内膜异位症，腹膜子宫内膜异位症和/或深部浸润性子宫内膜异位症相比，对照组和患者 子宫内膜该R 01的假设是，抑制这些新激酶靶点中的一种或多种将是有效的。 有效治疗子宫内膜异位症。在本提案中，我们概述了一个全面的方法， 在原代增生基质细胞和类器官培养物中功能性表征和靶向激酶 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（Baylor College of Medicine）药物发现中心（CDD），以确定新的激酶抑制剂， 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 一个超过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，可以为新药提供基础，以解决未满足的临床 子宫内膜异位症患者的需求。具体目的是：1）进行过表达激酶的靶标验证; 2)使用DEC-Tec来鉴定经验证激酶的新型小分子抑制剂并优化选择性， 高亲和力激酶结合剂的活性和稳定性;和3）评估优化的高亲和力激酶抑制剂在 体外和体内。确定子宫内膜异位症的新的有效疗法需要多方面的方法， 因此，需要加大努力来鉴定和筛选用于药物发现的新靶点。我们的方法是 将用于靶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， 通过完善的药物发现管道快速推进关键激酶靶点。我们的多学科 研究小组正在寻求发现新的化学实体，解决子宫内膜异位症的非激素轴， 独立治疗或在内分泌抑制剂中断期间作为序贯治疗。我们的DEC 该平台将帮助我们找到第一个未开发激酶的特异性抑制剂（一种主要的可药用激酶）。 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 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。