CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms Journal Article
| Authors: | Meyer, S.; Keller, M.; Chiu, S.; Koppikar, P.; Guryanova, O.; Rapaport, F.; Xu, K.; Manova, K.; Pankov, D.; O'reilly, R.; Kleppe, M.; Mckenney, A.; Shih, A.; 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, R.; Hoffman, R.; Sellers, W.; Hofmann, F.; Murakami, M.; Baffert, F.; Gaul, C.; Radimerski, T.; Levine, R. |
| Article Title: | CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms |
| Abstract: | 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. © 2015 Elsevier Inc. |
| Keywords: | controlled study; myelofibrosis; unclassified drug; drug efficacy; nonhuman; animal cell; mouse; allele; enzyme inhibition; animal experiment; animal model; enzyme phosphorylation; drug mechanism; murinae; myeloproliferative neoplasm; polycythemia vera; janus kinase 2 inhibitor; momelotinib; ruxolitinib; priority journal; article; fedratinib; chz 868; n,n dicyclopropyl 4 [(1,5 dimethyl 1h pyrazol 3 yl)amino] 6 ethyl 1,6 dihydro 1 methylimidazo[4,5 d]pyrrolo[2,3 b]pyridine 7 carboxamide |
| Journal Title: | Cancer Cell |
| Volume: | 28 |
| Issue: | 1 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2015-07-13 |
| Start Page: | 15 |
| End Page: | 28 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2015.06.006 |
| PROVIDER: | scopus |
| PMCID: | PMC4503933 |
| PUBMED: | 26175413 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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