Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo.
Discovery of HCD3514 as a potent EGFR inhibitor against C797S mutation in vitro and in vivo.
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发现 HCD3514 作为体外和体内 C797S 突变的有效 EGFR 抑制剂
DOI：
10.7150/jca.77788
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发表时间：
2023
影响因子：
3.9
通讯作者：
Xie H
中科院分区：
文献类型：
--
作者：
Lai M;Zhang T;Chen H;Song P;Tong L;Chen J;Liu Y;Ning Y;Feng F;Li Y;Tang H;Chen Y;Fang Y;Lu X;Geng M;Ding K;Yu K;Ding J;Xie H
Osimertinib(AZD9291)是第三代表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)，它显著提高了携带EGFRT790M突变的非小细胞肺癌(NSCLC)患者的生存率，这是导致对第一代EGFR TKI产生获得性耐药的主要机制。然而，AZD9291最终会产生耐药性，EGFRC797S突变被认为是主要的耐药机制。因此，开发针对C797S突变的新型EGFR第四代抑制剂以逆转获得性耐药性具有重要意义。在本研究中，我们确定HCD3514是一种针对C797S三重突变的新型EGFR第四代抑制剂。对EGFRL858R/T790M/C797S和EGFR19del/T790M/C797S突变有较强的抑制作用，IC50值分别为1.0和2.0 nM。HCD3514可剂量依赖性地抑制基因工程BaF3细胞和携带EGFRC797S三重突变的肿瘤细胞中EGFR的激活，从而有效地抑制细胞的增殖。此外，HCD3514诱导C797S三重突变细胞的凋亡率呈剂量依赖性增加，并伴有caspase-3和PARP裂解水平的升高。此外，HCD3514作为单一口服药物，通过降低EGFR的活性，抑制了EGFR19del/T790M/C797S移植瘤模型的生长。除EGFRC797S三重突变外，HCD3514还能有效和选择性地抑制EGFRT790M双突变(L858R/T790M和19del/T790M)。总之，HCD3514是一种高度选择性和有效的EGFR抑制剂，可对抗EGFRC797S三重突变和EGFRT790M双突变，并在临床前模型中被证实具有有效的抗肿瘤活性。
Osimertinib (AZD9291), a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), has significantly improved the survival of non-small cell lung cancer (NSCLC) patients with EGFRT790M mutation, the major mechanism of acquired resistance to first-generation EGFR TKI. However, resistance to AZD9291 arises eventually and EGFRC797S mutation was reported to be a major resistance mechanism. Thus, it is highly valuable to develop novel EGFR fourth-generation inhibitors targeting C797S mutation to override the acquired resistance. In this study, we identified HCD3514 as a novel EGFR fourth-generation inhibitors targeting C797S triple mutation. It strongly inhibited EGFRL858R/T790M/C797S and EGFR19del/T790M/C797S mutations with IC50 values of 1.0 and 2.0 nM, respectively. HCD3514 dose-dependently inhibited the activation of EGFR in both engineered BaF3 cells and tumor cells harboring EGFRC797S triple mutant and thus effectively suppressed the proliferation of the cells. Moreover, HCD3514 caused a dose-dependent increase of apoptosis in C797S triple mutant cells accompanied by increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, HCD3514 induced tumor growth inhibition in EGFR19del/T790M/C797S xenograft model as a single oral agent by decreasing the activation of EGFR. In addition to EGFRC797S triple mutations, HCD3514 also potently and selectively inhibited EGFRT790M double mutations (L858R/T790M and 19del/T790M). Collectively, HCD3514 is a highly selective and potent EGFR inhibitor against EGFRC797S triple mutations as well as EGFRT790M double mutations and is confirmed potently anti-tumor activity in preclinical models.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
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作者：
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作者：
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