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Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target

¹ Department of Bioengineering and ² Division of Applied Physics, Rice University; ³ Experimental Therapeutics and ⁴ Experimental Diagnostic Imaging, Chemistry Section, M. D. Anderson Cancer Center, Houston, Texas; and ⁵ Chemistry Department, Hacettepe University, Ankara, Turkey

Requests for reprints: Ariel Fernández, Department of Bioengineering, Rice University, Houston, TX 77005. Phone: 713-348-3681; E-mail: arifer{at}rice.edu.

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]