cKIT激酶抑制剂是胃肠间质瘤的主要临床一线治疗靶向药物，但是长期使用会导致cKIT激酶gatekeeper氨基酸残基T670I的突变从而引发耐药，而目前还未有能够克服cKIT-T670I突变并且与cKIT野生型之间取得选择性的抑制剂被报道。申请人在前期的研究中发现了一个能够在cKIT野生型与T670I突变之间取得一定选择性的先导化合物CHMFL-KIT-033，其抑制活性以及针对其它结构相近的激酶的选择性还有待改进。基于此，本项目拟利用II型激酶抑制剂的设计理念，通过药效片段组合等方法开展构效关系等研究，发展高选择性、高活性的能够克服cKIT T670I耐药性突变的激酶抑制剂，并探讨其作用机制，验证其作用效果，为进一步发展能够克服胃肠间质瘤的cKIT-T670I耐药性突变的临床药物奠定基础。

cKIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). There have been several cKIT kinase inhibitors approved for clinical applications in GISTs such as Imatinib and Sunitinib. However, after chronic treatment, drug-acquired point mutations such as T670I etc would cause drug resistance. Currently there is no reported inhibitor that could achieve selectivity between cKIT wt and the T670I drug resistant mutant. Recently, we discovered a potent type II cKIT-T670I kinase inhibitor CHMFL-KIT-033, which achieved 12-fold selectivity between cKIT wt and cKIT T670I mutant. However, it also potently inhibited some structurally similar kinases such as VEGFR2, FLT3 and PDGFR, etc. In order to avoid the off-target induced toxicity and to better elucidate the drug resistant mechanism, we propose to use CHMFL-KIT-033 as a lead compound for further medicinal modification. We will employ the fragment hybrid type II kinase inhibitor design approach to explore the SAR and develop highly potent and selective cKIT T670I kinase inhibitor. In addition, we will investigate the binding mechanism and evaluate its biological/pharmacological activities in vitro and in vivo, which will pave the way for developing new generation anti-drug resistance therapy for GISTs.