Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

• Published in: Leukemia Vol. 26; no. 2; pp. 280 - 288
• Main Authors: Purandare, A V, McDevitt, T M, Wan, H, You, D, Penhallow, B, Han, X, Vuppugalla, R, Zhang, Y, Ruepp, S U, Trainor, G L, Lombardo, L, Pedicord, D, Gottardis, M M, Ross-Macdonald, P, de Silva, H, Hosbach, J, Emanuel, S L, Blat, Y, Fitzpatrick, E, Taylor, T L, McIntyre, K W, Michaud, E, Mulligan, C, Lee, F Y, Woolfson, A, Lasho, T L, Pardanani, A, Tefferi, A, Lorenzi, M V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2012; Nature Publishing Group
• Subjects: Antigens; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferatives; Biological and medical sciences; Blotting, Western; Bone marrow; Cancer; Cancer Research; Care and treatment; Cell lines; Cell Proliferation - drug effects; Cells (biology); Chemical properties; Chemotherapy; Critical Care Medicine; Cytokines; Development and progression; Enzyme inhibitors; Enzymes; Gene Expression Profiling; Genetic aspects; Health aspects; Hematologic and hematopoietic diseases; Hematology; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Immunoglobulin G; Immunoglobulin M; Immunosuppression; Intensive; Internal Medicine; Janus kinase; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mutation; Myeloproliferative Disorders - enzymology; Myeloproliferative Disorders - pathology; Neoplasia; Neoplasms; Oncology; original-article; Pharmacodynamics; Pharmacology; Pharmacology. Drug treatments; Phosphotransferases; Progenitor cells; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Signal transduction; Signaling; Stat1 protein; Stem cells; Transcription; Tumors; United States; United States > US; immunosuppression; tyrosine kinase inhibitor; JAK2; STAT1; Antineoplastic agent; Human; JAK2 protein tyrosine kinase; Enzyme inhibitor; Malignant hemopathy; In vitro; JAK2V617F; Biological activity; Transcription factor STAT1; In vivo; Myeloproliferative syndrome; Chemotherapy; Treatment; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.292

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.