Therapeutic options against BCR-ABL1 T315I-positive chronic myelogenous leukemia

Alfonso Quintás-Cardama, Jorge Cortes

Research output: Contribution to journalReview article

79 Scopus citations

Abstract

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 T3151 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-T3151 therapies.

Original languageEnglish (US)
Pages (from-to)4392-4399
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number14
DOIs
StatePublished - Jul 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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