新型ASK1高选择性抑制剂的发现及其抗NASH活性研究

Apoptosis signal-regulated kinase 1 (ASK1) has emerged as an important target in nonalcoholic steatohepatitis (NASH) drug development pipeline. The structural classes of ASK1 inhibitors is still limited at present, and most of them show low drugability due to the poor kinase selectivity, which limits their study in NASH. In order to develop novel and highly selective ASK1 inhibitors, high throughput screen and rational drug design were used to implement the optimization of “Hit-to-lead” in the early stage of the project. The lead compound was found to be a highly potent and selective ASK1 inhibitor. Based on the previous research, the lead compound will be selected for rational optimization, and the characteristics of ligand binding domains in ASK1 will be comprehensively studied by combining biological assay and theoretical calculation for a further understanding of the structural basis of ASK1 in target specificity and ligand affinity, which will provide theoretical guidance for the design of new and highly selective ASK1 inhibitors. Meanwhile the representative compounds will be chosen for their biological studies, including effects on p38 and JNK signaling pathways, pharmacokinetic properties, anti-NASH activity in vivo and toxicological properties. The implementation of this project will help develop novel ASK1 inhibitors with high selectivity, and therefore providing more candidate molecules for the drug development of NASH.

凋亡信号调节激酶1（ASK1）是非酒精性脂肪性肝炎（NASH）药物研发管线上的重要靶点。目前已报道的ASK1抑制剂结构类型较少，且多数因激酶选择性差导致成药性不足，限制了其在NASH方面的研究。为开发新型ASK1高选择性抑制剂，本项目前期利用高通量筛选和合理药物设计，完成了“Hit-to-lead”优化，先导物对ASK1表现出高效选择性。本项目将在前期研究的基础上，对先导物进行合理的结构优化，结合活性测试和理论计算，对ASK1的配体结合域特征进行全面的研究，以进一步认知ASK1在靶标特异性、配体亲和力方面的结构基础，为新的ASK1高选择性抑制剂设计提供理论依据。同时项目还将对代表性化合物进行相关生物学研究，包括对P38和JNK信号通路的影响、药代性质、体内抗NASH活性及毒理性质。本项目的实施将有助于开发新型ASK1高选择性抑制剂，进而为NASH的药物开发提供更多的候选分子。

NASH是一种发病机制复杂的代谢性疾病，已成为肝硬化和肝癌的主要原因。ASK1是NASH药物研发管线上重要的靶点之一。然而，已报道的ASK1抑制剂的结构类型少、选择性欠佳，可作为临床候选的分子有限，因此开发结构新颖的ASK1高选择性抑制剂是当前一个迫切的科学任务。本项目利用高通量筛选和合理药物设计策略，设计并合成了87个结构全新的化合物。并对化合物进行了激酶活性和选择性测试。结合活性测试和分子对接模拟，本项目对ASK1抑制剂的构效关系进行了较为详细的研究，发现配体与铰链区的Val757形成氢键作用是发挥高活性的重要条件。此外，内部结合口袋中的Lys709是配体识别的重要位点，当配体与该氨基酸形成氢键作用时，活性得到提高。配体与活性位点中的Gln756形成氢键作用，可以同时提高化合物的活性和选择性。本项目通过进一步认知靶标特异性、配体亲和力方面的结构基础，从而为高选择性ASK1抑制剂的设计提供重要参考。此外，本项目选取代表性化合物进行了机制研究、体内代谢性质研究，评估了部分化合物评估化合物对NASH模型小鼠的干预治疗作用，部分化合物治疗效果较佳，为NASH的药物研发提供了更多的候选分子。

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