title: Rational drug redesign to overcome drug resistance in cancer therapy: imatinib moving target.
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.
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA. arifer@rice.edu
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
authors.forename: Angela
authors.initials: A
authors.lastname: Sanguino
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.forename: Alejandro
authors.initials: A
authors.lastname: Crespo
authors.forename: Eylem
authors.initials: E
authors.lastname: Ozturk
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Shimei
authors.initials: S
authors.lastname: Wang
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit