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

Abstract

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.

• Authors: A V Purandare, T M McDevitt, H Wan, D You, B Penhallow, X Han, R Vuppugalla, Y Zhang, S U Ruepp, G L Trainor, L Lombardo, D Pedicord, M M Gottardis, P Ross-Macdonald, H de Silva, J Hosbach, S L Emanuel, Y Blat, E Fitzpatrick, T L Taylor, K W McIntyre, E Michaud, C Mulligan, F Y Lee, A Woolfson, T L Lasho, A Pardanani, A Tefferi, M V Lorenzi
• Journal: Leukemia (Leukemia) Vol. 26 Issue 2 Pg. 280-8 (Feb 2012) ISSN: 1476-5551 [Electronic] England
• PMID: 22015772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide
• Protein Kinase Inhibitors
• JAK2 protein, human
• Janus Kinase 2

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Blotting, Western
• Cell Proliferation (drug effects)
• Gene Expression Profiling
• Heterocyclic Compounds, 3-Ring (chemistry, pharmacology)
• Humans
• Janus Kinase 2 (antagonists & inhibitors)
• Myeloproliferative Disorders (enzymology, pathology)
• Protein Kinase Inhibitors (chemistry, pharmacology)