2. Academic Validation
  3. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

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

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: christoph.gaul@novartis.com.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: dweinstock@partners.org.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18960
    99.56%, JAK2抑制剂
    JAK
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