TY - JOUR
T1 - Rational drug redesign to overcome drug resistance in cancer therapy
T2 - Imatinib moving target
AU - Fernández, Ariel
AU - Sanguino, Angela
AU - Peng, Zhenghong
AU - Crespo, Alejandro
AU - Ozturk, Eylem
AU - Zhang, Xi
AU - Wang, Shimei
AU - Bornmann, William
AU - Lopez-Berestein, Gabriel
PY - 2007/5/1
Y1 - 2007/5/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=34249290776&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0345
DO - 10.1158/0008-5472.CAN-07-0345
M3 - Article
C2 - 17483313
AN - SCOPUS:34249290776
SN - 0008-5472
VL - 67
SP - 4028
EP - 4033
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -