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.

Abstract	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.
Authors	A A Mian, A Rafiei, I Haberbosch, A Zeifman, I Titov, V Stroylov, A Metodieva, O Stroganov, F Novikov, B Brill, G Chilov, D Hoelzer, O G Ottmann, M Ruthardt
Journal	Leukemia (Leukemia) Vol. 29 Issue 5 Pg. 1104-14 (May 2015) ISSN: 1476-5551 [Electronic] England
PMID	25394714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	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
Topics	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, 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)

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