Reference Detail

Ref Type

Journal Article

PMID

(22015772)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	26	2	2012 Feb	280-8	Leukemia

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BMS-911543	BMS-911543	3	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BMS-911543		BMS 911543\|BMS911543	JAK2 Inhibitor - ATP competitive 15	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	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
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	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