Therapeutic Options Against <i>BCR-ABL1</i> T315I-Positive Chronic Myelogenous Leukemia

DOI PDF 1 Citations
  • Alfonso Quintás-Cardama
    Authors' Affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
  • Jorge Cortes
    Authors' Affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Description

<jats:title>Abstract</jats:title> <jats:p>Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of resistance continues to challenge the treatment of this disease. Mutations within the kinase domain of BCR-ABL1 constitute the most frequent mechanism of resistance in patients with chronic myelogenous leukemia treated with imatinib or the second generation tyrosine kinase inhibitors nilotinib and dasatinib. Of particular concern is the substitution of the threonine residue at the highly conserved gatekeeper residue 315 with a bulkier hydrophobic isoleucine amino acid. This mutation causes steric hindrance precluding the access ATP-competitive inhibitors to the ATP-binding pocket. To expedite the identification of strategies to override the resistance imposed by the T315I mutation, several strategies have been pursued, including the exploitation of BCR-ABL1 kinase sites distant from the ATP-binding pocket to cripple the kinase activity of the enzyme and inhibiting signaling pathways downstream from BCR-ABL1. Recent insights gained regarding the structural biology of T315I have led to the development of a variety of compounds against this mutant. We herein summarize the most clinically promising anti-T315I therapies.</jats:p>

Journal

  • Clinical Cancer Research

    Clinical Cancer Research 14 (14), 4392-4399, 2008-07-15

    American Association for Cancer Research (AACR)

Citations (1)*help

See more

Details 詳細情報について

Report a problem

Back to top