Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines

作者：Seohyun Son, Ahmed Elkamhawy, Anam Rana Gul, Ahmed A. Al‐Karmalawy, Radwan Alnajjar, Ahmed Abdeen, Samah F. Ibrahim, Saud O. Alshammari, Qamar A. Alshammari, Won Jun Choi, Tae Jung Park, Kyeong Lee · 发表于：Journal of Enzyme Inhibition and Medicinal Chemistry · 年份：2023 · DOI：10.1080/14756366.2023.2202358 · 被引用次数：12 · 研究领域：HER2/EGFR in Cancer Research、Lung Cancer Treatments and Mutations、14-3-3 protein interactions

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) protein tyrosine kinases co-expressed in various cancers such as ovarian, breast, colon, and prostate subtypes. Herein, new TAK-285 derivatives (9a–h) were synthesised, characterised, and biologically evaluated as dual EGFR/HER2 inhibitors. Compound 9f exhibited IC50 values of 2.3 nM over EGFR and 234 nM over HER2, which is 38-fold of staurosporine and 10-fold of TAK-285 over EGFR. Compound 9f also showed high selectivity profile when tested over a small kinase panel. Compounds 9a–h showed IC50 values in the range of 1.0–7.3 nM and 0.8–2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma.