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.

摘要 本更新补助金提案的目的是对低分子量的抗肿瘤药物进行临床前验证。 重量蛋白酪氨酸磷酸酶（LMPTP）作为肥胖相关糖尿病的治疗性治疗。 由胰岛素抵抗引起的糖尿病是肥胖相关疾病的主要原因。当前可用的 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， 是对降低胰岛素抗性的药剂的主要未满足的医学需求。靶向酪氨酸磷酸酶， 通过使胰岛素受体（IR）去磷酸化来抑制胰岛素信号传导被认为是一种潜在的策略， 通过使细胞对胰岛素的反应敏感来治疗2型糖尿病。酪氨酸磷酸酶LMPTP抑制 在人类中，遗传多态性通过IR的活化基序的去磷酸化来调节胰岛素信号传导。 编码低LMPTP活性与较低血糖水平相关。我们发现LMPTP是一个关键的启动子， 通过抑制肝脏中IR磷酸化来抑制肥胖诱导的胰岛素抵抗。携带全球和肝脏的小鼠- 然而，当喂食高脂肪饮食时，特异性LMPTP缺失小鼠体重增加与对照同窝小鼠相当 显示出显著改善的葡萄糖耐量和较低的空腹胰岛素水平。在上一次赠款期间， 资助周期，通过筛选分子库探针生产中心网络化学库 随后进行了广泛的点击率优化活动，我们利用LMPTP独特的结构特征， 产生一类新的抑制剂，其是口服生物可利用的，对LMPTP的选择性优于其他酪氨酸 磷酸酶，并降低胰岛素抵抗和恢复肥胖糖尿病小鼠的葡萄糖耐量。我们长久以来- 长期目标是将LMPTP抑制剂作为2型糖尿病患者的治疗选择推向临床。 因此，在这里，我们申请继续拨款资助，以收集临床前疗效和安全性数据，并进行 化学优化，以产生用于研究性新药使能研究的候选药物。我们将 通过追求3个具体目标来实现这一目标：1）验证LMPTP抑制剂在人体中的先导效应 肝细胞和肥胖诱导的糖尿病小鼠模型; 2）验证LMPTP抑制剂的安全性 在小鼠中; 3）通过结构引导药物的迭代循环产生优化的LMPTP抑制剂 化学.