Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

  • Cancer Cell. 2015 Jul 13;28(1):29-41. doi: 10.1016/j.ccell.2015.06.005.
Shuo-Chieh Wu  1 ,  Loretta S Li  2 ,  Nadja Kopp  1 ,  Joan Montero  1 ,  Bjoern Chapuy  1 ,  Akinori Yoda  1 ,  Amanda L Christie  1 ,  Huiyun Liu  1 ,  Alexandra Christodoulou  1 ,  Diederik van Bodegom  1 ,  Jordy van der Zwet  1 ,  Jacob V Layer  1 ,  Trevor Tivey  1 ,  Andrew A Lane  1 ,  Jeremy A Ryan  1 ,  Samuel Y Ng  1 ,  Daniel J DeAngelo  1 ,  Richard M Stone  1 ,  David Steensma  1 ,  Martha Wadleigh  1 ,  Marian Harris  3 ,  Emeline Mandon  4 ,  Nicolas Ebel  4 ,  Rita Andraos  4 ,  Vincent Romanet  4 ,  Arno Dölemeyer  4 ,  Dario Sterker  4 ,  Michael Zender  4 ,  Scott J Rodig  5 ,  Masato Murakami  4 ,  Francesco Hofmann  4 ,  Frank Kuo  5 ,  Michael J Eck  6 ,  Lewis B Silverman  3 ,  Stephen E Sallan  3 ,  Anthony Letai  1 ,  Fabienne Baffert  4 ,  Eric Vangrevelinghe  4 ,  Thomas Radimerski  4 ,  Christoph Gaul  7 ,  David M Weinstock  8
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4. Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • 5. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 7. Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. Electronic address: [email protected].
  • 8. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: [email protected].
PMID: 26175414 DOI: 10.1016/j.ccell.2015.06.005
Abstract

A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced Apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.

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