Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines.
Seohyun SonAhmed ElkamhawyAnam Rana GulAhmed Ali Al-KarmalawyRadwan AlnajjarAhmed AbdeenSamah F IbrahimSaud O AlshammariQamar A AlshammariWon Jun ChoiTae Jung ParkKyeong LeePublished in: Journal of enzyme inhibition and medicinal chemistry (2023)
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 IC 50 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 IC 50 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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- prostate cancer
- cell cycle
- molecular docking
- photodynamic therapy
- small cell lung cancer
- benign prostatic hyperplasia
- mycobacterium tuberculosis
- cell proliferation
- endothelial cells
- molecular dynamics simulations
- binding protein