CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

  • Cancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006.
Sara C Meyer  1 ,  Matthew D Keller  1 ,  Sophia Chiu  1 ,  Priya Koppikar  1 ,  Olga A Guryanova  1 ,  Franck Rapaport  1 ,  Ke Xu  2 ,  Katia Manova  2 ,  Dmitry Pankov  3 ,  Richard J O'Reilly  3 ,  Maria Kleppe  1 ,  Anna Sophia McKenney  1 ,  Alan H Shih  1 ,  Kaitlyn Shank  1 ,  Jihae Ahn  1 ,  Eftymia Papalexi  1 ,  Barbara Spitzer  1 ,  Nick Socci  4 ,  Agnes Viale  4 ,  Emeline Mandon  5 ,  Nicolas Ebel  5 ,  Rita Andraos  5 ,  Joëlle Rubert  5 ,  Ernesta Dammassa  5 ,  Vincent Romanet  5 ,  Arno Dölemeyer  5 ,  Michael Zender  5 ,  Melanie Heinlein  5 ,  Raajit Rampal  6 ,  Rona Singer Weinberg  7 ,  Ronald Hoffman  8 ,  William R Sellers  9 ,  Francesco Hofmann  5 ,  Masato Murakami  5 ,  Fabienne Baffert  5 ,  Christoph Gaul  5 ,  Thomas Radimerski  10 ,  Ross L Levine  11
Affiliations
  • 1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2. Molecular Cytology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5. Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
  • 6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7. New York Blood Center, New York, NY 10065, USA.
  • 8. Department of Medicine, Mount Sinai Hospital, New York, NY 10029, USA.
  • 9. Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • 10. Novartis Institutes for Biomedical Research, Basel 4056, Switzerland. Electronic address: [email protected].
  • 11. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 26175413 DOI: 10.1016/j.ccell.2015.06.006
Abstract

Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK Inhibitor, would demonstrate activity in JAK Inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK Inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18960
    CHZ868
    98.69%, JAK2 Inhibitor
    target: JAK
    Research Areas: Cancer