靶向EGFR T790M降解剂的设计、合成及其抗非小细胞肺癌活性的研究

The mutation of EGFR T790M related resistance has becoming the new coming clinical dilemma, although inhibitors of EGFR has gained great success in clinic in treating Non-small cell lung cancer (NSCLC). The third selectively irreversible EGFR T790M tyrosine kinase inhibitors (such as osimertinib) has been approved by the U.S. Food and Drug Administration (FDA). However, the C797S mutation induces resistance to osimertinib. Inducing protein degradation is a new strategy of exploring anticancer therapy. EGFR T790M mutation has been demonstrated as a driving force for resistant NSCLC cell growth, whereas it is not detected in normal human tissues. EGFR T790M is an ideal target to overcome the acquired resistance of NSCLC patients without adverse toxicities. Our project is intended to take XTF-262 (highly selective inhibitor targeting EGFR T790M synthesized in the former stage by our group, the selective ratio of EGFR T790M towards EGFR wild type is almost 200 times) as a targeting ligand, linked with E3 Ligase recruitment ligand or hydrophobic group by a chemical linker, in order to selectively inducing EGFR T790M degradation. Then such chimeras would selectively kill NSCLC cells harboring EGFR T790M mutant. We will conduct new synthesis and modification of small-molecule degraders that capable of inducing target protein (EGFR T790M) degradation, then analysis structure-activity relationship and study the mechanism of degradation. In most recently, we have tried to synthesize series of such degraders. Several of them can degrade EGFR T790M. Our study will provide several candidate compounds, and provide bases of inducing EGFR T790M degradation to overcome NSCLC acquired resistance in clinic.

EGFR抑制剂用于临床治疗非小细胞肺癌（NSCLC）获得成功，但引起EGFR T790M突变诱发耐药成为临床难题。第三代EGFR T790M非可逆抑制剂osimertinib等已被美国FDA批准上市，然而导致EGFR C797S突变产生新的耐药。诱导蛋白降解是当前抗肿瘤药物开发的新策略，EGFR T790M突变体仅存在于病人肿瘤组织中是进行蛋白降解的理想靶标。课题组前期设计合成多个全新高选择性EGFR T790M抑制剂，代表化合物XTF-262对EGFR T790M突变型选择性相对于EGFR野生型接近200倍。本研究将以XTF-262为先导化合物，引入不同的E3连接酶配体小分子或疏水基团，选择性诱导EGFR T790M的降解，从而杀伤携带EGFR T790M突变的NSCLC细胞。前期已初步合成的降解剂可降解EGFR T790M，预期为临床克服NSCLC突变耐药提供候选化合物和新思路。

EGFR抑制剂用于临床治疗非小细胞肺癌（NSCLC）获得成功，但EGFR T790M突变诱发耐药成为新的临床医学问题。第三代EGFR T790M非可逆抑制剂AZD9291等已被美国FDA批准上市，然而引起EGFR C797S突变导致耐药。诱导蛋白降解是当前抗肿瘤药物开发的新策略，EGFR T790M突变体仅存在于病人肿瘤组织中是进行蛋白降解的理想靶标。本项目我们参考PROTAC技术先固定头部活性分子为前期得到的EGFR T790M高选择性靶向抑制剂 XTF-262，通过各种连接键与不同E3连接酶配体或疏水标签基团共价连接，设计合成一类具有 EGFRT790M蛋白降解活性的小分子降解剂针对这批化合物展开活性研究发现，已合成的化合物对H1975有显著杀伤。项目按计划如期执行，并已基本完成系列EGFR降解剂设计合成和活性的构效关系研究工作，并发现一批具有靶向EGFR T790M的活性降解剂，选择性抑制和降解EGFR T790M。通过本课题发表SCI论文4篇，申请专利一项，积极推进成果转化和应用培养研究生2名。已完成或达到预期目标。