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• W2108696175 abstract "Abstract Protein kinases are central targets for drug-based cancer treatment. To avoid functional impairment, the cell develops mechanisms of drug resistance, primarily based on adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. We approach the problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening, cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. [Cancer Res 2007;67(9):4028–33]" @default.
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• W2108696175 date "2007-05-01" @default.
• W2108696175 modified "2023-10-17" @default.
• W2108696175 title "Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target" @default.
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• W2108696175 doi "https://doi.org/10.1158/0008-5472.can-07-0345" @default.
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