Discovery of Benzoxazepines as a New Class of PIM1 Kinase Inhibitors Through Structure Based Virtual Screening, Biochemical Evaluation and Cytotoxicity Studies

Abstract PIM kinase is a serine/threonine protein kinase implicated in human cancers because it promotes cell proliferation while inhibiting apoptosis and is a crucial target for malignancy. In the present study, we used 700000 commercially available Chembridge small molecules library for structure‐based drug discovery to identify novel potent PIM1 kinase inhibitors. Based on the virtual screening results, ten compounds were chosen and screened enzymatically at 10 μM. Out of ten compounds, only two compounds, 22876894 (61 %) and 58626268 (63 %), inhibited PIM1 kinase. Subsequently, the enzymatic IC 50 value for compounds 22876894 and 58626268 was calculated and found to be 0.8 μM and 3.9 μM. Cell viability was evaluated on human malignant cell lines HCT‐116 (colorectal carcinoma), U‐2OS (osteosarcoma), and non‐cancerous hTERT‐RPE‐1. It was found that compound 22876894 possessed significant inhibitory activity against HCT‐116 (IC 50 =12.1 μM), U‐2OS (IC 50 =23.2 μM), and hTERT‐RPE‐1 (IC 50 =12.7 μM) cell lines. The compound 58626268 possessed significant inhibitory activities against HCT‐116 (IC 50 =28.1 μM), U‐2OS (IC 50 =23.5 μM), and hTERT‐RPE‐1 (IC 50 =21 μM) cell lines. Further, the molecular dynamics simulation of identified compounds (22876894 and 58626268) was performed. Based on kinase profiling, cytotoxicity studies, and molecular dynamics simulation results, we claim 5‐{[7‐(1‐benzothien‐3‐yl)‐9‐hydroxy‐2,3‐dihydro‐1,4‐benzoxazepin‐4(5H)‐yl]carbonyl}pyridin‐2(1H)‐one (22876894) and 4‐(2‐aminoisonicotinoyl)‐7‐(1‐benzothien‐3‐yl)‐2,3,4,5‐tetrahydro‐1,4‐benzoxazepin‐9‐ol (58626268) as a selective and potential PIM1 kinase inhibitors.