Reconnecting new tetrahydrobenzothieno-4-pyrimidine amides as potent PIM-1 kinase inhibitors via an integrated ligand, machine learning model and structure based scaffold hopping: In vitro anti-tumor investigations

PIM1 has been known to be one of the prolific molecular target in the discovery of new potential Anticancer drugs due to its engagement in activation of cell proliferation and anti-apoptosis. Till date not a single drug is in the market that targets PIM-1 kinase and hence this kinase poses prime requisite for discovery of novel inhibitors. A pharmacophore based virtual screening technique was employed to discover compounds bearing of tetrahydrobenzothieno-4-pyrimidine amide scaffold. A series of molecules have been synthesized bearing aforementioned scaffold, characterized and screened against a number of cell lines, PIM1 kinase inhibitory potential and Apoptosis activity. This lead to identification of novel compound 7 k as a potent inhibitor of PIM-1 kinase that exceptionally inhibited the proliferation of HT-29, PC3 and A549 carcinoma cells. 7 k significantly induced Apoptosis in HT-29 cell line and furthermore, 7 k inhibited PIM-1 kinase with inhibitory activity of 74.15 ± 2.90%. 7 k profoundly formed hydrogen bond with Asp128 and showed high stability in the molecular dynamics simulations. Compound 7 k portrayed an excellent in silico ADME and drug likeness attributes with predictive absorption percentile of 91.15. Aforesaid outcomes revealed that 7 k recognized as promising lead candidate for development of novel Pim kinases inhibitors as Anticancer agents.

Apoptosis; HT-29; Molecular docking; Molecular dynamics simulations; PIM-1 kinase; Pharmacophore modelling.