This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Quintás-Cardama, A. Articles by Cortes, J. PubMed PubMed Citation Articles by Quintás-Cardama, A. Articles by Cortes, J. Related Collections Clinical Research Clinical Research: Clinical Trials

Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia

Authors' Affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Alfonso Quintás-Cardama, University of Texas M. D. Anderson Cancer Center, Department of Leukemia, Unit 428, 1515 Holcombe Boulevard. Houston, TX 77030. Phone: 713-792-0077; Fax: 713-794-4297; E-mail: aquintas{at}mdanderson.org.

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.