Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	28	1	2015 Jul 13	15-28	Cancer Cell

URL

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	5	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CHZ868			JAK2 Inhibitor 19	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