Small molecule inhibitors of LMPTP: an obesity drug target

LMPTP 小分子抑制剂：肥胖药物靶点

• 批准号: 10669954
• 负责人: Nunzio Bottini
• 金额: $ 52.66万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669954
• 关键词: Small; molecule; inhibitors; LMPTP; obesity

ABSTRACT The objective of this renewal grant proposal is to perform preclinical validation of an inhibitor of the low molecular weight protein tyrosine phosphatase (LMPTP) as a therapeutic treatment for obesity-associated diabetes. Diabetes caused by insulin resistance is a major cause of obesity-associated morbidity. The currently available anti-diabetic treatments are often insufficient to maintain glycemic control in type 2 diabetes patients; thus there is a major unmet medical need for agents that lower insulin resistance. Targeting tyrosine phosphatases that inhibit insulin signaling by dephosphorylating the insulin receptor (IR) is considered a potential strategy for treating type 2 diabetes by sensitizing the cellular response to insulin. The tyrosine phosphatase LMPTP inhibits insulin signaling by dephosphorylation of the activation motif of the IR. In humans, genetic polymorphisms encoding low LMPTP activity associate with lower glycemic levels. We discovered that LMPTP is a key promoter of obesity-induced insulin resistance by inhibiting IR phosphorylation in the liver. Mice carrying global and liver- specific LMPTP deletion gain comparable weight to control littermate mice when fed a high-fat diet, however display substantially improved glucose tolerance and lower fasting insulin levels. During the previous grant funding cycle, through a screening of the Molecular Libraries Probe Production Centers Network chemical library followed by an extensive hit-to-lead optimization campaign, we exploited unique structural features of LMPTP to generate a new class of inhibitors that is orally bioavailable, exclusively selective for LMPTP over other tyrosine phosphatases, and lowers insulin resistance and restores glucose tolerance in obese diabetic mice. Our long- term goal is to advance an LMPTP inhibitor to the clinic as a therapeutic option for patients with type 2 diabetes. Thus here we apply for continued grant funding to collect preclinical efficacy and safety data and perform chemical optimization in order to generate a candidate for investigational new drug-enabling studies. We will accomplish this objective by pursuing 3 Specific Aims: 1) validation of the LMPTP inhibitor lead efficacy in human hepatocytes and in mouse models of obesity-induced diabetes; 2) validation of the LMPTP inhibitor lead safety in mice; 3) generation of an optimized LMPTP inhibitor lead through iterative cycles of structure-guided medicinal chemistry.

抽象的 该更新授予建议的目的是对低分子的抑制剂进行临床前验证 体重蛋白酪氨酸磷酸酶（LMPTP）作为肥胖相关糖尿病的治疗治疗。 胰岛素抵抗引起的糖尿病是肥胖相关发病率的主要原因。当前可用 抗糖尿病治疗通常不足以维持2型糖尿病患者的血糖控制；因此 是降低胰岛素抵抗的药物的主要未满足医疗需求。靶向酪氨酸磷酸酶 通过去磷酸化胰岛素受体（IR）被认为是抑制胰岛素信号传导被认为是潜在的策略 通过使细胞对胰岛素的反应敏感，治疗2型糖尿病。酪氨酸磷酸酶LMPTP抑制 IR的活化基序的去磷酸化通过胰岛素信号传导。在人类中，遗传多态性 编码低血糖水平的低LMPTP活性。我们发现LMPTP是关键启动子 肥胖引起的胰岛素抵抗通过抑制肝脏中的IR磷酸化。携带全球和肝的小鼠 - 喂养高脂饮食时，特定的LMPTP缺失与控制同窝小鼠的重量相当，但是 显示大大提高的葡萄糖耐量和降低的空腹胰岛素水平。在上一个赠款期间 筹资周期，通过筛选分子库探测生产中心网络化学库 其次是广泛的命中率优化活动，我们利用LMPTP的独特结构特征 产生一种新的抑制剂，这些抑制剂可口服可生物利用，仅针对其他酪氨酸而选择LMPTP 磷酸酶，并降低胰岛素抵抗并恢复肥胖糖尿病小鼠的葡萄糖耐受性。我们的长期 术语目标是将LMPTP抑制剂推向诊所，作为2型糖尿病患者的治疗选择。 因此，在这里，我们申请持续的赠款资金来收集临床前效力和安全数据并执行 化学优化是为了产生研究新药物研究的候选者。我们将 通过追求3个特定目标来实现这一目标：1）验证人类LMPTP抑制剂铅功效 肝细胞和肥胖引起的糖尿病的小鼠模型； 2）验证LMPTP抑制剂铅安全 在老鼠中； 3）通过结构引导药用的迭代周期产生优化的LMPTP抑制剂。 化学。