Journal ArticleDOI
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
TLDR
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 and illustrates how molecular insight into kinase inhibitors resistance can guide the design of second-generation targeted therapies.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-driven disease and inhibits proliferation of BCR-ABL-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.read more
Citations
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Journal ArticleDOI
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Susumu Kobayashi,Titus J. Boggon,Tajhal Dayaram,Pasi A. Jänne,Olivier Kocher,Matthew Meyerson,Bruce E. Johnson,Michael J. Eck,Daniel G. Tenen,Balazs Halmos,Balazs Halmos +10 more
TL;DR: In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.
Journal ArticleDOI
Cancer drug resistance: an evolving paradigm
TL;DR: There are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
Journal ArticleDOI
Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain
William Pao,Vincent A. Miller,Katerina Politi,Gregory J. Riely,Romel Somwar,Maureen F. Zakowski,Mark G. Kris,Harold E. Varmus +7 more
TL;DR: Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib, which should help guide the search for more effective therapy against a specific subset of lung cancers.
Journal ArticleDOI
Targeting cancer with small molecule kinase inhibitors
TL;DR: This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors, and discusses the current challenges in the field.
Journal ArticleDOI
A small molecule-kinase interaction map for clinical kinase inhibitors.
Miles A. Fabian,William H. Biggs,Daniel K. Treiber,Corey E. Atteridge,Mihai Azimioara,Mihai Azimioara,Michael G. Benedetti,Michael G. Benedetti,Todd A. Carter,Pietro Ciceri,Philip T. Edeen,Mark Floyd,Julia M. Ford,Margaret Galvin,Jay L Gerlach,Jay L Gerlach,Robert M. Grotzfeld,Sanna Herrgard,Darren E. Insko,Michael A Insko,Andiliy G. Lai,Jean-Michel Lélias,Shamal A. Mehta,Zdravko V. Milanov,Anne Marie Velasco,Lisa M. Wodicka,Hitesh K. Patel,Patrick P. Zarrinkar,David J. Lockhart +28 more
TL;DR: An efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases is described, which represents a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
References
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Journal ArticleDOI
Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia
Brian J. Druker,Moshe Talpaz,Debra Resta,Bin Peng,Elisabeth Buchdunger,John Ford,Nicholas B. Lydon,Hagop M. Kantarjian,Renaud Capdeville,Sayuri Ohno-Jones,Charles L. Sawyers +10 more
TL;DR: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed and demonstrates the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Journal ArticleDOI
Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.
Brian J. Druker,Shu Tamura,Elisabeth Buchdunger,Sayuri Ohno,Gerald M. Segal,Shane Fanning,Jürg Zimmermann,Nicholas B. Lydon +7 more
TL;DR: A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein and it was found that this compound may be useful in the treatment of bcr–abl–positive leukemias.
Journal ArticleDOI
Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia
Stephen G. O'Brien,François Guilhot,Richard A. Larson,Insa Gathmann,Michele Baccarani,Francisco Cervantes,Jan J. Cornelissen,Thomas Fischer,Andreas Hochhaus,Timothy P. Hughes,Klaus Lechner,Johan Lanng Nielsen,Philippe Rousselot,Josy Reiffers,Giuseppe Saglio,John D. Shepherd,Bengt Simonsson,Alois Gratwohl,John M. Goldman,Hagop M. Kantarjian,Kerry Taylor,Gregor Verhoef,Ann E. Bolton,Renaud Capdeville,Brian J. Druker +24 more
TL;DR: Imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML and was better tolerated than combination therapy.
Journal ArticleDOI
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
Mercedes E. Gorre,Mansoor Mohammed,Katharine Ellwood,Nicholas C. Hsu,Ron Paquette,P. Nagesh Rao,Charles L. Sawyers +6 more
TL;DR: It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.
Journal ArticleDOI
Structural mechanism for STI-571 inhibition of abelson tyrosine kinase
Thomas Schindler,William Bornmann,Patricia Pellicena,W. Todd Miller,Bayard D. Clarkson,John Kuriyan +5 more
TL;DR: The results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
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