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 本次更新拨款提案的目的是对低分子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方法。 由胰岛素抵抗引起的糖尿病是肥胖相关发病的主要原因。目前可用的 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；因此有 是降低胰岛素抵抗药物的一个主要未满足的医疗需求。靶向酪氨酸磷酸酶 通过去磷酸化胰岛素受体（IR）来抑制胰岛素信号传导被认为是一种潜在的策略 通过提高细胞对胰岛素的反应来治疗 2 型糖尿病。酪氨酸磷酸酶 LMPTP 抑制 通过 IR 激活基序的去磷酸化来传递胰岛素信号。在人类中，基因多态性 编码低 LMPTP 活性与较低的血糖水平相关。我们发现LMPTP是一个关键的启动子 通过抑制肝脏中的 IR 磷酸化来治疗肥胖引起的胰岛素抵抗。携带全球和肝脏的小鼠 然而，当喂食高脂肪饮食时，特定 LMPTP 缺失的体重增加与对照同窝小鼠相当 显示出显着改善的葡萄糖耐量和较低的空腹胰岛素水平。在上一次补助期间 资助周期，通过分子图书馆探针生产中心网络化学图书馆的筛选 随后进行了广泛的从命中到先导的优化活动，我们利用 LMPTP 的独特结构特征 产生一类具有口服生物利用度的新型抑制剂，对 LMPTP 的选择性优于其他酪氨酸 磷酸酶，降低肥胖糖尿病小鼠的胰岛素抵抗并恢复葡萄糖耐量。我们的长期 短期目标是将 LMPTP 抑制剂推向临床，作为 2 型糖尿病患者的治疗选择。 因此，我们在此申请继续拨款，以收集临床前疗效和安全性数据并执行 化学优化，以产生用于新药研究的候选药物。我们将 通过追求 3 个具体目标来实现这一目标：1) 验证 LMPTP 抑制剂先导药物在人体中的功效 肝细胞和肥胖引起的糖尿病小鼠模型； 2) LMPTP抑制剂先导物安全性验证 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。