Rational modification of semaxanib and sunitinib for developing a tumor growth inhibitor targeting ATP binding site of tyrosine kinase |
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Authors: | Jagroop Kaur Baljit Kaur Palwinder Singh |
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Institution: | Department of Chemistry, UGC Sponsored Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India |
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Abstract: | Analysis of the crystal structure of tyrosine kinase in complexation with an ATP analogue, supplemented with the molecular docking studies of semaxanib and sunitinib in the ATP binding site of the enzyme enabled us to make design of a series of tyrosine kinase inhibitors. The combination of pyrrole and indolinone in one molecule and placement of appropriate substituent thereof made the molecule compatible for the hydrophobic sub-pocket of the enzyme. Screening of the compounds over 60 cell line panel of human tumor cell lines identified compound 3a that exhibited GI50 35?nM and 63?nM against MCF7 and MDA-MB-468 cell lines of breast cancer. |
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Keywords: | Pyrrole Indole Molecular modeling Tyrosine kinase Anticancer |
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