Kinase inhibitors in chronic myelogenous leukemia.
The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate launched the era of molecular targeted therapy and constitutes a milestone in oncology history. However, despite impressive cytogenetic response rates achieved with this agent in patients with chronic myelogenous leukemia (CML) in chronic phase, those with advanced-stage CML frequently obtain more modest responses that are in many instances of short duration. Several mechanisms of resistance to imatinib have been described among patients that develop clinical resistance to imatinib. Point mutations in the Bcr-Abl kinase domain that impair the ability of imatinib to inhibit the kinase activity represent the leading cause of resistance. Several approaches are being pursued to overcome these mutations. In addition, many other protein kinases implicated in signaling transduction downstream Bcr-Abl play critical roles in the pathogenesis of CML, thus representing potential therapeutic targets. Multiple compounds are being screened to identify inhibitors of these kinases. This article focuses on the current state of development of new kinase inhibitors for the therapy of CML.
Quintás-Cardama
Alfonso
A
Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cortes
Jorge
J
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides; D000069439:Dasatinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib