Novel small-molecule MDM2 inhibitor as a potential anticancer agent for gastric and breast cancer

Breast and gastric cancers are among the most common cancers worldwide and are strongly influenced by the p53–MDM2 axis, yet clinical development of MDM2 inhibitors has been limited by drug resistance and poor efficacy. We investigated K1, a quinazoline derivative, which demonstrated potent anticancer activity with an IC50 value of 18.5µM in AGS and 19µM in MCF7 cell lines 72 h post treatment, and it also significantly reduced their clonogenic potential. Transcriptomic data show that K1 targets multiple stress pathways in distinct cellular compartments. In MCF7, ribosomal stress genes (RPL11, RPL23, RPS7, RPL26) and ER stress markers (DDIT3, ATF4, EIF2AK3) were upregulated. In addition, the expression of apoptotic protein mediators (PMAIP1, BBC3) and DNA damage regulators (CDKN1A, CDKN2D, FHIT) was also upregulated, whereas in AGS cells, mitochondrial dysfunction and mitophagy indicators (PINK1, PRDX3, PARK7), oxidative stress genes (CYP1A1, BACH1), and apoptotic regulators (FOXO3, RHOB, STAT1) showed increased expression. Elevated expression of mitotic stress and spindle assembly checkpoint genes (PLK1, CCNB1, CDC20, BUB1, MAD2L) leads to G2/M arrest and spindle disruption. This compartment-specific activity indicates a spatial biology perspective, linking gene expression changes to localized stress within the tumor environment. K1 causes nuclear fragmentation, cytoskeletal disruption, ROS generation, mitochondrial dysfunction, and DNA damage. In vitro studies indicated decreased MDM2 with increased p53 and p21 expression in MCF7, while AGS showed a decline in MDM2 and p53, with increased p21 expression. Despite the differences in response, both cell lines ultimately culminated in apoptosis. Molecular docking of K1 with MDM2 exhibited key molecular interactions, binding conformation, and stable dynamics. Our data identifies K1 as a promising anticancer candidate that activates compartment-specific, spatially distinct stress responses, leading to apoptosis in two distinct cancer types.