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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CHZ868||JAK2 Inhibitor 17||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|
|MPL W515L||hematologic cancer||sensitive||CHZ868||Preclinical||Actionable||In a preclinical study, CHZ868 inhibited proliferation of bone marrow cell lines expressing MPL W515L in culture, including cells with decreased response to Type I JAK inhibitors due to chronic exposure (PMID: 26175413).||26175413|
|MPL W515L||myelofibrosis||sensitive||CHZ868||Preclinical||Actionable||In a preclinical study, CHZ868 demonstrated efficacy in a mouse model of MPL W515L induced myelofibrosis (PMID: 26175413).||26175413|