Strategies to circumvent the T315I gatekeeper mutation in the Bcr-Abl tyrosine kinase

Prithviraj Bose, Haeseong Park, Jawad Al-Khafaji, Steven Grant

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, most often due to point mutations in the Bcr-Abl tyrosine kinase (TK) domain, is quite common. Of these, the T315I "gatekeeper" mutation is resistant to all currently registered Bcr-Abl TK inhibitors (TKIs) with the notable exception of ponatinib (Iclusig™), which was very recently approved by the United States Food and Drug Administration (FDA). Besides ponatinib, numerous strategies have been developed to circumvent this problem. These include the protein synthesis inhibitor omacetaxine (Synribo®), and "switch-control" inhibitors. Dual Bcr-Abl and aurora kinase inhibitors represent another promising strategy. Finally, several promising synergistic combinations, such as TKIs with histone deacetylase inhibitors (HDACIs), warrant attention.

Original languageEnglish
Pages (from-to)18-20
Number of pages3
JournalLeukemia Research Reports
Issue number1
StatePublished - 2013


  • Bcr-Abl
  • Gatekeeper mutations
  • HDAC inhibitors
  • T315I
  • Tyrosine kinase inhibitors


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