@article {Shah399, author = {Shah, Neil P. and Tran, Chris and Lee, Francis Y. and Chen, Ping and Norris, Derek and Sawyers, Charles L.}, title = {Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor}, volume = {305}, number = {5682}, pages = {399--401}, year = {2004}, doi = {10.1126/science.1099480}, publisher = {American Association for the Advancement of Science}, abstract = {Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL{\textendash}driven disease and inhibits proliferation of BCR-ABL{\textendash}positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.}, issn = {0036-8075}, URL = {https://science.sciencemag.org/content/305/5682/399}, eprint = {https://science.sciencemag.org/content/305/5682/399.full.pdf}, journal = {Science} }