Design, synthesis, and biological evaluation of novel CDK4/6 and BRD4 dual inhibitors for treatment of KRAS-mutant NSCLC

CDK4/6 is the candidate therapeutic target for KRAS-mutant NSCLC. However, its frequent primary and acquired resistance limits its potential clinical application. Recently it had been shown that BRD4 up-regulation induced conferred resistance of KRAS-mutant NSCLC cells to CDK4/6 inhibitor, and BRD4 Inhibitor synergized with CDK4/6 inhibitor induced senescence in KRAS-mutant NSCLC tumors and cells, meanwhile, the combined therapy extended survival of the KRAS-mutant NSCLC mouse model. Thus, a series of CDK4/6 and BRD4 dual inhibitors were prepared to target KRAS-mutant NSCLC. Among these compounds, PJ2 exhibited potent antiproliferative effects against KRAS-mutant NSCLC cells NCI-H358 (IC₅₀ = 0.34 ± 0.01 μM) and A549 (IC₅₀ = 0.31 ± 0.04 μM), and had excellent inhibitory effects on CDK4, CDK6, BRD4(BD1) and BRD4(BD2), and IC₅₀ values were 168.75 ± 46.32 nM, 292.45 ± 11.67 nM, 23.17 ± 3.61 nM and 3.12 ± 0.15 nM, respectively. Mechanism research indicated that PJ2 induced cell cycle arrest, senescence and Apoptosis through ROS-mediated DNA damage. Furthermore, PJ2 could effectively suppress the migration and invasion of NCI-H358 cells. These results proved that developing potent CDK4/6 and BRD4 dual inhibitors was a promising strategy for the KRAS-mutant NSCLC therapy.

Antitumor; BRD4; CDK4/6; KRAS-Mutant NSCLC; Senescence.