PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation

Leukemia. 2015 May;29(5):1104-14. doi: 10.1038/leu.2014.326. Epub 2014 Nov 14.


Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Mutational Analysis
  • Female
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Mutagenesis
  • Mutation*
  • Point Mutation
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyridazines / pharmacology
  • Pyridines / pharmacology*
  • Translocation, Genetic
  • Triazoles / pharmacology*
  • Xenograft Model Antitumor Assays
  • fms-Like Tyrosine Kinase 3 / metabolism


  • Antigens, Ly
  • Antineoplastic Agents
  • Imidazoles
  • Ly6a protein, mouse
  • Membrane Proteins
  • PF-114
  • Pyridazines
  • Pyridines
  • Triazoles
  • ponatinib
  • FLT3 protein, human
  • Proto-Oncogene Proteins c-kit
  • fms-Like Tyrosine Kinase 3
  • Fusion Proteins, bcr-abl