Development of first-in-class antagonists of the retinoid pathway as novel oral therapies for Type 2 Diabetes

项目摘要： 类维生素A通路是人类生物学中的一个中心调节通路， 在过去的20年里，当膳食维生素A被转运到靶组织时， 被氧化为全反式维甲酸（atRA），然后结合RARα/β/γ核受体。此绑定 导致转录调节，这是众所周知的影响各种分化状态， 细胞和组织。在代谢性疾病中，ALDH 1a 3是负责最终合成的关键酶。 类维生素A配体的步骤，也已被确定为主要的胰腺β细胞标志物之一 治疗2型糖尿病许多研究表明，ALDH 1a 3蛋白水平或酶活性与细胞增殖有关。 在2型糖尿病中丧失产生胰岛素能力的失败/去分化β细胞的特异性标志物 糖尿病人而类维生素A信号一直是啮齿动物和人类感兴趣的途径 糖尿病，发表的研究还没有确定是否类维生素A信号，从而ALDH 1a 3 是2型糖尿病的诱因。 我们的初步发现工作表明ALDH 1a 3是β细胞去分化的驱动因子 在2型糖尿病中观察到，因此可以提供一个靶点，其抑制可以提供持久的治疗 对糖尿病患者的影响与2型糖尿病社区的利益相关者进行了讨论， 显示出对恢复胰腺功能的疾病修饰疗法的相当大的兴趣， 目前的治疗方法在控制血糖水平的活性方面受到限制 而不是影响胰腺健康。因此，为了扭转类型的预期上升， 2世界各地的糖尿病患者，需要下一代药物组合来恢复胰腺β 细胞正常分化状态。 利用专有的化学平台，Kayothera是第一个开发出铅的小组。 针对ALDH 1a 3的抑制剂显示出优异的效力和特异性，同时避免了 类维生素A途径中其他药物开发项目的药理学责任。我们的疗法 在抑制类维生素A途径方面显示出强的效力（<5 nM细胞，比对照组提高200倍）。 公开的分子），无脱靶活性，高代谢稳定性，优异的口服药代动力学 性质和有前途的体内毒理学。在这里，我们建议提名IND开发 通过剂量范围探索研究和PD/疗效模型确定候选药物。这项研究成果 该提案将推动一流的治疗走向临床试验，目的是恢复胰腺癌。 为数百万有需要的患者提供健康保障。

Project Summary: The retinoid pathway is a central regulatory pathway in human biology that has been considered undruggable for the last 20 years. It is activated when dietary vitamin A is transported to target tissues, is oxidized to all-trans retinoic acid (atRA), and then binds the RARα/β/γ nuclear receptors. This binding results in transcriptional regulation that is best known to influence the differentiation state of various cells and tissues. In metabolic disorders, ALDH1a3 is a key enzyme responsible for the final synthetic step of the retinoid ligand, and has also been identified as one of the principal pancreatic β cell markers for Type 2 diabetes. Numerous studies have shown that ALDH1a3 protein levels or enzymatic activity is a specific marker for failing/dedifferentiated β cells that lose the ability to produce insulin in Type 2 diabetics. Whereas retinoid signaling has long been a pathway of interest in both rodent and human diabetes, published studies have not established whether or not retinoid signaling and thus ALDH1a3 are drivers of Type 2 diabetes. Our initial discovery work suggests that ALDH1a3 is a driver of the β cell dedifferentiation observed in Type 2 diabetes and thus may offer a target whose inhibition can offer durable treatment effects for diabetics. Discussions with stakeholders across the Type 2 Diabetes community have demonstrated considerable interest in disease-modifying therapies that restore pancreatic function as there is broad recognition that current therapies are limited in activity to controlling blood glucose levels and insulin sensitivity rather than affecting pancreatic health. Thus, to reverse the projected rise of Type 2 diabetics across the world, next generation drug combinations are needed that restore pancreatic β cells to their normal differentiation status. Utilizing proprietary chemistry platforms, Kayothera is the first group to have developed lead inhibitors against ALDH1a3 that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs in the retinoid pathway. Our therapies show strong potency in inhibiting the retinoid pathway (<5 nM cellular, a 200-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate an IND development candidate through dose-range finding studies and PD/efficacy models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of restoring pancreatic health to millions of patients in need.