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Ref Type Journal Article
PMID (26175413)
Authors Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, Xu K, Manova K, Pankov D, O'Reilly RJ, Kleppe M, McKenney AS, Shih AH, Shank K, Ahn J, Papalexi E, Spitzer B, Socci N, Viale A, Mandon E, Ebel N, Andraos R, Rubert J, Dammassa E, Romanet V, Dölemeyer A, Zender M, Heinlein M, Rampal R, Weinberg RS, Hoffman R, Sellers WR, Hofmann F, Murakami M, Baffert F, Gaul C, Radimerski T, Levine RL
Title CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.
Journal Cancer cell
Vol 28
Issue 1
Date 2015 Jul 13
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CHZ868 CHZ868 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CHZ868 JAK2 Inhibitor 16 CHZ868 is a type II JAK2 inhibitor, which stabilizes JAK2 in the inactive conformation resulting in decreased downstream signaling and potentially leading to decreased tumor cell growth (PMID: 26175413, PMID: 30498775).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F bone marrow cancer sensitive CHZ868 Preclinical Actionable In a preclinical study, CHZ868 inhibited proliferation of myeloproliferative neoplasm cells harboring JAK2 V617F , including cells with decreased response to Type I JAK inhibitors following chronic exposure, and decreased mutant allele burden in a mouse polycythemia vera model expressing JAK2 V617F (PMID: 26175413). 26175413