Preclinical Studies Demonstrate Activity of Type II JAK2 Inhibitor in B-Cell ALL
Laboratory and animal tests of the type II inhibitor CHZ868, which stabilizes the kinase domain in an inactive conformation, are showing that the compound is highly potent against B-cell acute lymphoblastic leukemias (ALLs) with CRLF2 rearrangements. When combined with dexamethasone, CHZ868 induced apoptosis in JAK2-dependent B-cell ALLs and further improved in vivo survival compared to CHZ868 alone. The study data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other cancers, according to the study authors. The study by Wu et al is published in Cancer Cell.
Study Methodology
The researchers launched a discovery program to identify type II JAK2 inhibitors with improved potency, selectivity, and physiocochemical properties. A variety of cancers depend on JAK2 signaling, including the high-risk subset of B-cell ALLs with CRLF2 rearrangements. To improve the efficacy of JAK2 inhibition in B-cell ALL, the researchers developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation.
The researchers then tested the agent in laboratory samples of B-cell ALL with CRLF2 rearrangement in mice with the disease and in mice implanted with human B-cell ALL tissue.
Study Findings
The testing found that CHZ868 potentially suppressed the growth of CRLF2-rearranged human B-cell ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-cell ALL. In addition, CHZ868 combined with the corticosteroid dexamethasone “synergistically induced apoptosis in JAK2-dependent [B-cell 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,” concluded the study authors.
“In each case [of the mice with human or murine B-cell ALL], we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David M. Weinstock, MD, a coauthor of the study and Attending Physician, Medical Oncology Service at Dana-Farber Cancer Institute, in a statement. “When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive and the animals lived longer than they did with CHZ868 alone…. JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma. The success of CHZ868 in [B-cell ALL] suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”
Christoph Gaul, PhD, of Novartis Institute for Biomedical Research, is the corresponding author of this study.
Funding for this study was provided by the Dana-Farber/Novartis Drug Discovery Program, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. For full disclosures of the study authors, visit www.cell.com/cancer-cell.
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