Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
J Med Chem. 2024 Feb 22;67(4):2777-2801. doi: 10.1021/acs.jmedchem.3c01934. Epub 2024 Feb 7.
Activation of the alternative pathways and abnormal signaling transduction are frequently observed in third-generation EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors)-resistant patients. Wherein, hyperphosphorylation of ACK1 contributes to EGFR-TKIs acquired resistance. Dual inhibition of EGFR and ACK1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFR/ACK1 dual-targeting compound with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFR (IC = 23 nM) and ACK1 (IC = 263 nM). The cocrystal and docking analysis showed that occupied the ATP binding pockets of EGFR and ACK1. Moreover, showed potent antiproliferative activities against the H1975 cells, MCF-7 cells and osimertinib-resistant cells AZDR. Further, showed significant antitumor effects and good safety in ADZR xenograft-bearing mice. Taken together, was a potent dual inhibitor of EGFR/ACK1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.
第三代 EGFR-TKIs（表皮生长因子受体酪氨酸激酶抑制剂）耐药患者常出现旁路激活和异常信号转导。其中，ACK1 的过度磷酸化有助于 EGFR-TKIs 获得耐药性。双重抑制 EGFR 和 ACK1 可能会提高治疗效果并克服肺癌治疗中的耐药性。在这里，我们鉴定了一种具有氨基喹唑啉骨架的 EGFR/ACK1 双重靶向化合物，该化合物对 EGFR（IC = 23 nM）和 ACK1（IC = 263 nM）具有优异的抑制活性。共晶和对接分析表明，化合物占据了 EGFR 和 ACK1 的 ATP 结合口袋。此外，化合物对 H1975 细胞、MCF-7 细胞和奥希替尼耐药细胞 AZDR 具有很强的增殖抑制活性。进一步，化合物在 ADZR 荷瘤小鼠中表现出显著的抗肿瘤作用和良好的安全性。综上所述，化合物是一种有效的 EGFR/ACK1 双重抑制剂，有望成为克服 EGFR 靶向治疗中奥希替尼获得性耐药的潜在先导化合物。
