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

• DOI: 10.1158/aacr.edb-can-07-0345
• Publication Date: 2008-11-17T14:28:59Z
• Authors: A. Fernandez; A. Sanguino; Z. Peng; A. Crespo; E. Ozturk; X. Zhang; S. Wang; W. Bornmann; G. Lopez-Berestein
• Keywords: Models, Molecular; 0301 basic medicine; 0303 health sciences; Gastrointestinal Stromal Tumors; Protein Conformation; Antineoplastic Agents; Piperazines; 3. Good health; Kinetics; Proto-Oncogene Proteins c-kit; Structure-Activity Relationship; 03 medical and health sciences; Pyrimidines; Drug Resistance, Neoplasm; Cell Line, Tumor; Drug Design; Benzamides; Mutation; Imatinib Mesylate; Humans; Phosphorylation; Protein Kinase Inhibitors

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]