Targeting RAGE/DIAPH1: Novel Therapeutic Strategy for Diabetic Complications

摘要 糖尿病的并发症，特别是伤口愈合受损和糖尿病相关的肾病，有 1型和2型糖尿病患者发病和死亡的主要原因。狂暴的胞外结构域 是异质的，并且RAGE配体可以结合在这些结构域上空间上不同的位置，从而表明 使用针对胞外区域的小分子或抗体可能是无效的。我们有 发现RAGE的细胞质尾巴(CtRAGE)与细胞内的福尔曼分子的相互作用， DIAPH1在RAGE介导的信号转导中起着至关重要的作用。我们之前进行了一次高通量筛选 研究了59,000种化合物，目的是阻断ctRAGE与DIAPH1的相互作用。我们发现了两条线索 符合类药物特性关键标准的系列(LS)；从LSII系列中脱颖而出的RAGE229 由于疗效、良好的药代动力学特征和前景，可能成为临床开发的领先者 早期脱靶和毒性测试。体内的疗效也被证明，因为服用RAGE229 在小鼠迟发性超敏反应实验中减轻炎症，缩小心肌梗死范围 结扎和再灌流糖尿病小鼠左冠状动脉前降支，并减少 糖尿病小鼠肾脏病理和创面愈合受损的多个参数 对车辆，在雄性和雌性小鼠中都是如此。然而，在后期测试中，RAGE229在 迷你艾姆斯测试。为了解决这一问题，我们已经准备了RAGE229的新类似物；这些类似物 保留效力，但在Mini-Ames测试中为阴性。此外，我们在以下方面取得了重大进展 在LSI中开发后备候选对象。重要的是，LSI中的一种铅基准化合物检测为阴性 在Mini-Ames测试中也是如此。我们老牌的多学科团队现在已经做好了向前迈进的准备 在这个关键时刻积极寻找LSII的主要候选分子和终极LSI的后备LSI 糖尿病并发症的临床进展。我们的药物发现目标，得到广泛的初步支持 数据是：1)确定LSII的有效、选择性和安全的候选类似物；以及2)开发LSI备份 候选人使用不同的脚手架来减轻我们愤怒计划的风险。如果成功，我们的工作将为 一类新型糖尿病疾病改良剂的开发和临床试验阶段 并发症。

Abstract The complications of diabetes, particularly impaired wound healing and diabetes-associated nephropathy, are major causes of morbidity and mortality in patients with types 1 and 2 diabetes. The RAGE extracellular domains are heterogeneous and RAGE ligands may bind at spatially-distinct sites on these domains, thereby indicating that the use of small molecules or antibodies targeted to the extracellular domains, may be ineffective. We have discovered that the interaction of the cytoplasmic tail of RAGE (ctRAGE) with the intracellular formin molecule, DIAPH1, is essential for RAGE-mediated signal transduction. We previously performed a high-throughput screen of >59,000 compounds with the goal to block the interaction of ctRAGE with DIAPH1. We identified two lead series (LS) that fulfill key criteria for drug-like properties; from one of the series, LSII, RAGE229 emerged as a plausible lead for clinical development because of efficacy, favorable pharmacokinetic profile and promising early-stage off-target and toxicity testing. In vivo efficacy was also demonstrated, as administration of RAGE229 attenuated inflammation in a delayed type hypersensitivity experiment in mice, reduced myocardial infarct size upon ligation and reperfusion of the left anterior descending coronary artery in diabetic mice, and reduced multiple parameters of diabetes-associated kidney pathology and impaired wound healing in diabetic mice, all versus vehicle, in both male and female mice. However, in late-stage testing, RAGE229 tested positive in the Mini-AMES test. To address this liability, we have already prepared new analogs of RAGE229; these analogs retain potency but are negative in the Mini-AMES test. In addition, we have made significant progress in developing back-up candidates in the LS I. Importantly, a lead benchmark compound within LSI tested negative in the Mini-AMES test as well. Our established, multi-disciplinary team is now well-poised to move forward aggressively at this critical juncture to identify lead candidate molecules for LSII and the back-up LSI for ultimate clinical development for diabetic complications. Our drug discovery goals, supported by extensive preliminary data are: 1) to identify potent, selective, and safe candidate analogs of LSII; and 2) to develop LSI backup candidates with a different scaffold to mitigate risk to our RAGE program. If successful, our work will set the stage for the development and clinical testing of a novel class of disease-modifying agents for diabetic complications.