EGFR的快速反馈激活是目前应用Vemurafenib（FDA批准的首个B-RafV600E 抑制剂）治疗结肠直肠癌患者耐药的主要原因，该耐药问题目前临床上还没有得到有效解决。使用B-RafV600E与EGFR激酶的双重抑制剂治疗结肠直肠癌患者有望为解决该耐药问题提供一条可行途经。我们通过基于结构的合理药物设计技术，成功设计了一类全新的具有优异的抑制B-RafV600E与EGFR激酶活性的杂环芳基酰胺类化合物。先导化合物CY02787在体外表现出了良好的抗肿瘤活性，对B-Raf（V600E）激酶的IC50值约为31nM，对EGRF激酶的IC50值约为44nM，对结肠癌细胞HT29（B-RafV600E，EGFR）的IC50为0.75μM。本项目将以CY02787为先导化合物进行系统构效关系研究、作用机制和体内外抗肿瘤活性研究。

It was reported that the reason of unresponsiveness of colon cancer to Vemurafenib is the feedback activation of EGFR. Currently, there are no targeted treatment options available for B-Raf(V600E) mutant colon cancer and it might benefit from B-Raf and EGFR dual-inhibitors. As B-Raf(V600E) and EGFR sharing the similar ATP-binding domains, we successfully designed and synthesized of CY02787 as B-Raf and EGFR dual-inhibitor. CY02787 showed potent activity against B-Raf(V600E) and EGFR as well as colon cancer cell HT29, with IC50 value 31nM, 44nM and 0.75μM, respectively. This program focus on the systemic structure-activity relationship study, in vitro and in vivo anti-tumor activity and mechanism study of CY02787-like derivatives and eventually develop drug-like candidates for the pre-clinical test.