Small molecule inhibitors of LMPTP: an obesity drug target

摘要 这项续期拨款提案的目标是对一种低分子药物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药物。 胰岛素抵抗引起的糖尿病是肥胖相关发病率的主要原因。当前可用的 抗糖尿病治疗往往不足以维持2型糖尿病患者的血糖控制；因此 是降低胰岛素抵抗药物的主要未得到满足的医疗需求。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转导被认为是一种潜在的 通过敏化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 IR激活基序去磷酸化的胰岛素信号转导。在人类中，基因多态 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IR的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，当喂食高脂饮食时，特定LMPTP缺失的小鼠体重增加与对照小鼠相当 表现出显著改善的葡萄糖耐量和较低的空腹胰岛素水平。在上一次拨款期间 资助周期，通过筛选分子文库探测生产中心网络化工库 在广泛的点击到领先的优化活动之后，我们利用LMPTP的独特结构特性来 产生一类新的口服生物利用型抑制剂，对LMPTP具有比其他酪氨酸更高的选择性 并降低肥胖糖尿病小鼠的胰岛素抵抗和恢复葡萄糖耐量。我们的长- 长期目标是将LMPTP抑制剂推向临床，作为2型糖尿病患者的治疗选择。 因此，我们在这里申请继续拨款，以收集临床前疗效和安全性数据，并执行 化学优化，以产生一个研究性新药使能研究的候选者。我们会 通过追求3个具体目标来实现这一目标：1)验证LMPTP抑制剂在人类体内的有效性 肝细胞和肥胖诱导的糖尿病小鼠模型；2)LMPTP抑制剂铅安全性的验证 在小鼠体内；3)通过结构导向药物的迭代循环产生优化的LMPTP抑制剂Lead 化学反应。

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.