基于DCLK1的新型抗急性炎症先导物发现和优化研究

急性肺损伤、脓毒症等急性炎症病死率高，目前尚无有效治疗药物，临床上亟待研发新靶点新机制的抗急性炎症药物。从蛋白激酶中发现和确证抗急性炎症新药靶是本领域的前沿方向。双肾上腺皮质激素样激酶1（DCLK1）是一种潜在的抗急性炎症药靶，但目前尚无有效治疗急性炎症的DCLK1小分子抑制剂。因而，DCLK1能否作为成药性抗急性炎症药靶有待验证，抗急性炎症DCLK1小分子抑制剂有待发现。前期，本课题通过基于结构的合理药物设计策略发现了高活性化合物8n，在分子、细胞、动物水平具有优秀的DCLK1抑制活性和体内外抗急性炎症活性，初步验证了研究设想。在此基础上，本课题拟基于DCLK1深入开展合理药物设计，阐明构效关系和作用机制，提升化合物成药性，获得高活性候选药物，为验证基于DCLK1开发抗急性炎症创新药物奠定理论和物质基础。

Acute inflammatory diseases, including acute lung injury (ALI) and sepsis, remain the leading cause of mortality in critical care patients globally. However, there is no specific and effective therapeutic agents available to treat these diseases. It is highly desirable to develop novel anti-acute inflammatory agent with new target and mechanism. Discovery of novel anti-inflammatory agents targeting kinase represents a frontier direction in this field. Doublecortin-like kinase 1 (DCLK1) is a type of serine/threonine kinase and has shown the potential to be an anti-acute inflammatory drug target. However, no anti-acute inflammatory small molecule DCLK1 inhibitors have been reported so far. Therefore, the anti-acute inflammatory druggability of DCLK1 and its small molecule inhibitors remain validated. Previously, a highly potent anti-acute inflammatory lead compound 8n was identified by structure-based rational drug design strategy. Biological activity studies confirmed the lead compound 8n showed excellent DCLK1 inhibitory activity as well as anti-acute inflammatory potency, which preliminary validated the scientific hypothesis at molecular, cellular and animal level. Inspired by these results, this project will focus on the discovery of small molecule DCLK1 inhibitor by structure-based rational drug design, elucidating the SARs and the mechanism of action and improving the drug-like properties of 8n. As a result, this project aims to discover highly active candidate and provides a basis for the development of DCLK1-based novel anti-acute inflammatory agents.