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 (2015-07-16)

Shuo-Chieh Wu, Loretta S Li, Nadja Kopp, Joan Montero, Bjoern Chapuy, Akinori Yoda, Amanda L Christie, Huiyun Liu, Alexandra Christodoulou, Diederik van Bodegom, Jordy van der Zwet, Jacob V Layer, Trevor Tivey, Andrew A Lane, Jeremy A Ryan, Samuel Y Ng, Daniel J DeAngelo, Richard M Stone, David Steensma, Martha Wadleigh, Marian Harris, Emeline Mandon, Nicolas Ebel, Rita Andraos, Vincent Romanet, Arno Dölemeyer, Dario Sterker, Michael Zender, Scott J Rodig, Masato Murakami, Francesco Hofmann, Frank Kuo, Michael J Eck, Lewis B Silverman, Stephen E Sallan, Anthony Letai, Fabienne Baffert, Eric Vangrevelinghe, Thomas Radimerski, Christoph Gaul, David M Weinstock

PMID26175414

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.

MATERIALS

Product Number

Brand

Product Description

T9026

Sigma-Aldrich

Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid

SML3399

Sigma-Aldrich

CHZ868, ≥98% (HPLC)