Abstract
Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were incorporated to fit into the ATP binding site and extend to the adjacent allosteric site and selectively inhibit protein kinases. This design led to potential selective inhibition of ABL1, CDK1/Cyclin A1, FAK, and SRC kinase by 30–59%. Cytotoxicity was improved by ∼50 times for the optimized lead (10b; IC50 = 40 nM) against breast cancer (MCF-7) cells. Many compounds revealed potential cytotoxicity against ovarian (A2780) and colon carcinoma (HCT116) cells of ∼10–30 time improvement (IC50 5–17 nM). The results of the Annexin-V/PI apoptotic assay demonstrated that many compounds induced significantly early (89–146%) and a dramatically late (556–1180%) cell death in comparison to the vehicle control of MCF-7 cells. SAR indicated that 5-deazaalloxazines have a higher selectivity for Abl-1 and FAK kinases than alloxazines. The correlations between GoldScore fitness into FAK and SRC kinases and IC50 against MCF-7 and A2780 cells were considerable (R2: 0.86–0.98).
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•IC50 of the lead compound was remarkably improved by computational design using PTKs.•Many alloxazines revealed potent inhibition of ABL1, CDK1/Cyclin A1, FAK and SRC.•Significant late (up to1180%) and early apoptosis (up to 145.6%) were demonstrated.•The correlation between docking scores and IC50 were highly considerable (R2: 0.98).•5-Deazaalloxazine have the highest selectivity for Abl-1 and FAK kinases.