LAUSR

New derivatives of 2‐phenylquinazolin‐4(3H)‐one were designed, synthesized, and biologically evaluated as potent allosteric kinase inhibitors with in situ cytotoxicity against MCF‐7 and HepG2 cells. Compounds 15 and 18 among the proposed compounds showed promising antiproliferative activity against MCF‐7 (IC50 = 1.35 µM) and HepG2 cells (IC50 = 3.24 µM), comparable to sorafenib, with IC50 values of 3.04, 2.93 µM, respectively, according to in situ cytotoxicity testing. Comparing compounds 15 and 18 to sorafenib, the in vitro VEGFR‐2 inhibitory activity displayed encouraging selective efficacy with IC50 values of 13, 67, and 30 nM, respectively. Results of VEGFR‐2 inhibition at various ATP concentrations proved that there was no statistically significant difference between the IC50 values, which improved the non‐ATP competitive binding. Compound 15 caused apoptotic breast cancer cell death with 55.11‐fold cell‐cycle arrest at the S‐phase, where it affected the apoptosis‐mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the antiapoptotic gene Bcl‐2. A molecular docking study was conducted to confirm the binding of the designed compounds to the allosteric site of VEGFR‐2 in DFG‐out mode, leaving the ATP‐binding pocket unoccupied when superimposed to the pose of sorafenib. The designed molecules showed resealable binding affinity toward the DFG loop and the allosteric site. Hence, the 2‐phenylquinazolin‐4(3H)‐one derivative constitutes intriguing starting points for designing apoptotic‐inducing drugs.