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.
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.
Department of Hematology, Goethe University, Frankfurt, Germany.
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Mian
Department of Hematology, Goethe University, Frankfurt, Germany.
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Rafiei
Department of Hematology, Goethe University, Frankfurt, Germany.
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Haberbosch
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Zeifman
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Titov
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Stroylov
Department of Hematology, Goethe University, Frankfurt, Germany.
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Metodieva
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Stroganov
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Novikov
Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.
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Brill
1] Fusion Pharma, LLC, Moscow, Russian Federation [2] Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
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Chilov
Department of Hematology, Goethe University, Frankfurt, Germany.
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Hoelzer
Department of Hematology, Goethe University, Frankfurt, Germany.
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Ottmann
Department of Hematology, Goethe University, Frankfurt, Germany.
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Ruthardt
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016296:Mutagenesis; D009154:Mutation; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D014178:Translocation, Genetic; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
D000950:Antigens, Ly; D000970:Antineoplastic Agents; D007093:Imidazoles; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C000599898:PF-114; D011724:Pyridazines; D011725:Pyridines; D014230:Triazoles; C545373:ponatinib; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl