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|Ref Type||Journal Article|
|Authors||Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, Lombardo L, Pedicord D, Gottardis MM, Ross-Macdonald P, de Silva H, Hosbach J, Emanuel SL, Blat Y, Fitzpatrick E, Taylor TL, McIntyre KW, Michaud E, Mulligan C, Lee FY, Woolfson A, Lasho TL, Pardanani A, Tefferi A, Lorenzi MV|
|Title||Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|BMS-911543||BMS 911543|BMS911543||JAK2 Inhibitor - ATP competitive 14||BMS-911543 is a selective ATP-competitive inhibitor of JAK2, which may decrease tumor cell proliferation (PMID: 22015772, PMID: 26288683, PMID: 30388009).|
|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||essential thrombocythemia||sensitive||BMS-911543||Preclinical - Cell culture||Actionable||In a preclinical study, BMS-911543 inhibited proliferation and induced apoptosis in an essential thrombocythemia cell line harboring JAK2 V617F in culture (PMID: 22015772).||22015772|
|JAK2 V617F||hematologic cancer||sensitive||BMS-911543||Preclinical - Cell culture||Actionable||In a preclinical study, BMS-911543 inhibited proliferation of transformed cells expressing JAK2 V617F in culture (PMID: 22015772).||22015772|
|JAK2 V617F||myeloproliferative neoplasm||sensitive||BMS-911543||Preclinical - Cell culture||Actionable||In a preclinical study, BMS-911543 inhibited colony growth in myeloproliferative neoplasm patient-derived hematopoetic progenitor cells harboring JAK2 V617F in culture (PMID: 22015772).||22015772|