Objective

Statement of Research: Tyrosine kinase inhibitors and their potential in the clinical application are well documented by dramatic examples like Gleevec, Iressa, and Nexavar etc. Several tyrosine kinase inhibitors are undergoing human trials and several are in the pipeline of drug discovery. Quick selection of epidemiologically relevant, drugable tyrosine kinase targets coupled with efficient lead finding and optimization needs more intervention in the area of high throughput cancer genome-based molecular therapeutics. All these concerted efforts may pave the silver lining to tailor-made personalized cancer therapeutics. Experimental & Theoretical Orientation: Keeping in view their importance, twenty new substituted indolin-2-one containing imine derivatives (2a-2t) were synthesized and docked with eight different tyrosine kinase enzymes (Aurora A Kinase PDB: 3FDN, Aurora B Kinase PDB: 2VRX, human Abl kinase PDB: 3CS9, human CDK6-V CYCLIN PDB: 2EUF, C-MET PDB: 4XMO, EGFR PDB: 1M17, Focal Adhesion Kinase PDB: 2JKK, human VEGFR-2 PDB: 3VHE). On the basis of docking results, Abl kinase target was selected out of all kinase targets for the in-vitro enzyme assay. Enzymatic inhibition assay was performed for all twenty compounds using Abl kinase enzyme inhibition assay kit and IC₅₀ was obtained for all compounds. Simultaneously, all compounds were sent to NCI, USA for sixty-cell line based anticancer screening, out of which fifteen compounds were selected for one dose anticancer assay. Findings: Compounds 2a (NSC: D-795068/1) and 2g (NSC: D-795071/1) were found potent during one dose anticancer screening and fulfilled the specified threshold for growth inhibition criteria of NCI and further selected for full panel five dose assay at 10-fold dilutions of five different concentrations. Both compounds 2a and 2g displayed Mid GI₅₀ values of 1.69 µM & 1.54 µM respectively against the cell lines of Leukemia, Non-Small Cell Lung Cancer, Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer, Renal Cancer, Prostate Cancer and Breast Cancer. Conclusion: The results were found even better than the standard used (Fluorouracil) by NCI. In silico studies and ADME prediction also supported the potential of these compounds as tyrosine kinase inhibitors. It is expected that Tyrosine Kinase inhibition by the said compounds may deliberate a substantial therapeutic benefit over existing treatments for cancer.