Investigation of the Therapeutic Potential of Fibroblast Activation Protein Inhibition in Type 2 Diabetes

项目摘要 在全球范围内，2型糖尿病（T2 D）患者人数接近3.5亿[1]。 随着这一数字的迅速上升，也迫切需要有效的治疗方法来治疗这种疾病。 增加。研究工作在治疗选择方面取得了重大进展，包括 二肽基肽酶4（DPP 4）抑制剂、胰高血糖素样肽-1（GLP-1）模拟物和 SGLT 2抑制剂可改善葡萄糖刺激的胰岛素分泌并降低血糖。尽管 这些进展，在葡萄糖正常化和预防糖尿病方面仍然存在差距。 目前的治疗方法无法解决的人群并发症， 数以百万计的患者血糖控制不足和不安全。 最近，一种称为成纤维细胞活化蛋白（FAP）的蛋白酶已经成为一种潜在的 治疗T2 D和肥胖症的靶点[2]。FAP是与DPP 4最密切相关的酶[3， 4]，一个有效的药物靶点。DPP 4的多种药理学抑制剂现在被广泛用于 2型糖尿病患者[5]。以前对FAP的兴趣集中在其作为癌症靶点的潜力上 由于其在上皮肿瘤中的上调而治疗[6]。然而，最近的FAP特异性活性测定， 已经确定了FAP在循环中的活性，以及在代谢中起作用的几种组织中的活性。 条例[7]。最有趣的是，对FAP基因敲除小鼠（Fap-/-） 证明了a）显著防止饮食诱导的肥胖和B）改善的肥胖， 表型发现与在整体DPP 4敲除（Dpp 4-/-）小鼠中描述的那些相似[2]。 重要的是，FAP具有独特的内肽酶活性，这表明其酶靶点是 与DPP 4不同。因此，FAP抑制可能提供治疗糖尿病的新途径。 我们已经独立产生了突变的Fap-/-小鼠，使我们能够确定代谢 表型由遗传性FAP缺陷引起。补充实验将利用一个强大的， 特异性FAP抑制剂，化合物5057，以确定药理学FAP抑制是否 产生与在Fap-/-小鼠中观察到的相同的代谢益处。Fap-/-小鼠和野生型小鼠治疗 与化合物5057将用于确定生理机制（和FAP底物） 这是FAP失活的代谢益处的基础。我们希望这项研究将奠定 为治疗T2 D的一类新药的临床试验奠定了基础。

Project Summary Globally, the number of people with type 2 diabetes mellitus (T2D) is approaching 350 million [1]. With this number rapidly rising, the urgent need for effective therapeutics to treat this disease is also increasing. Research efforts have produced significant advances in treatment options, including the introduction of dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) mimetics and SGLT2 inhibitors to improve glucose-stimulated insulin secretion and lower blood glucose. Despite these advances, there remains a gap in the normalization of glucose and the prevention of complications among the population that current treatments have been unable to address, leaving millions of patients with insufficient and unsafe levels of glucose control. Recently, a protease enzyme called fibroblast activation protein (FAP) has emerged as a potential target for the treatment of T2D and obesity [2]. FAP is the most closely related enzyme to DPP4 [3, 4], a validated drug target. Multiple pharmacological inhibitors of DPP4 are now widely used in patients with T2D [5]. Previous interest in FAP has focused on its potential as a target for cancer therapy due to its upregulation in epithelial tumors [6]. However, recent FAP-specific activity assays have identified FAP activity in the circulation, as well as in several tissues with roles in metabolic regulation [7]. Most intriguingly, preliminary characterization of a global FAP knockout (Fap-/-) mouse demonstrated a) significant protection against diet-induced obesity and b) improved glycemia, phenotypic findings similar to those described in the global DPP4 knockout (Dpp4-/-) mouse [2]. Importantly, FAP has a unique endopeptidase activity, suggesting that its enzymatic targets are different from those of DPP4. Thus, FAP inhibition may provide a novel route to treatment of diabetes. We have independently generated mutant Fap-/- mice, enabling us to determine the metabolic phenotype ensuing from genetic FAP deficiency. Complementary experiments will utilize a potent and specific FAP inhibitor, compound 5057, to determine whether pharmacological FAP inhibition produces the same metabolic benefits observed in Fap-/- mice. Fap-/- mice and wild-type mice treated with compound 5057 will be employed to identify physiological mechanisms (and FAP substrates) underlying the metabolic benefits of FAP inactivation. We are hopeful that this research will lay the groundwork for clinical testing of a new class of drugs for the treatment of T2D.