BMS-911543 - CAS 1271022-90-2
Catalog number: B0084-457828
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Targets:
JAK
Description:
BMS-911543 is an orally available small molecule targeting a subset of Janus-associated kinase (JAK) with potential antineoplastic activity. JAK2 inhibitor BMS-911543 selectively inhibits JAK2, thereby preventing the JAK/STAT (signal transducer and activator of transcription) signaling cascade, including activation of STAT3. This may lead to an induction of tumor cell apoptosis and a decrease in cellular proliferation. JAK2, often upregulated or mutated in a variety of cancer cells, mediates STAT3 activation and plays a key role in tumor cell proliferation and survival.
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Catalog Number Size Price Stock Quantity
B0084-457828 20 mg $298 In stock
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Synonyms:
BMS-911543
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Current Developer:
Bristol-Myers Squibb
1.Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer.
Mace TA1, Shakya R2, Elnaggar O1, Wilson K3, Komar HM1, Yang J1, Pitarresi JR4, Young GS5, Ostrowski MC4, Ludwig T4, Bekaii-Saab T1, Bloomston M6, Lesinski GB1. Oncotarget. 2015 Dec 29;6(42):44509-22. doi: 10.18632/oncotarget.6332.
The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant Kras to drive initiation and progression of PDAC in murine models. We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit anti-tumor activity against PDAC and decrease immune suppressive features of the disease. We used an aggressive genetically engineered PDAC model with mutant KrasG12D, tp53R270H, and Brca1 alleles (KPC-Brca1 mice). Mice with confirmed tumor burden were treated orally with vehicle or 30 mg/kg BMS-911543 daily for 14 days. Histologic analysis of pancreata from treated mice revealed fewer foci of adenocarcinoma and significantly decreased Ki67+ cells versus controls. In vivo administration of BMS-911543 significantly reduced pSTAT5 and FoxP3 positive cells within the pancreas, but did not alter STAT3 phosphorylation. Continuous dosing of KPC-Brca1 mice with BMS-911543 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.
2.Ni-Catalyzed C-H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543.
Fitzgerald MA1, Soltani O1, Wei C1, Skliar D1, Zheng B1, Li J1, Albrecht J1, Schmidt M1, Mahoney M1, Fox RJ1, Tran K1, Zhu K1, Eastgate MD1. J Org Chem. 2015 Jun 19;80(12):6001-11. doi: 10.1021/acs.joc.5b00572. Epub 2015 May 1.
BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C-N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.
3.Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm.
Pomicter AD1, Eiring AM1, Senina AV1, Zabriskie MS1, Marvin JE2, Prchal JT3, O'Hare T4, Deininger MW5. Exp Hematol. 2015 Jul;43(7):537-45.e1-11. doi: 10.1016/j.exphem.2015.03.006. Epub 2015 Apr 24.
Activation of Janus kinase 2 (JAK2), frequently as a result of the JAK2(V617F) mutation, is a characteristic feature of the classical myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and myelofibrosis, and it is thought to be responsible for the constitutional symptoms associated with these diseases. BMS-911543 is a JAK2-selective inhibitor that induces apoptosis in JAK2-dependent cell lines and inhibits the growth of CD34(+) progenitor cells from patients with JAK2(V617F)-positive MPN. To explore the clinical potential of this inhibitor, we tested BMS-911543 in a murine retroviral transduction-transplantation model of JAK2(V617F) MPN. Treatment was initiated at two dose levels (3 mg/kg and 10 mg/kg) when the hematocrit exceeded 70%. Following the first week, white blood cell counts were reduced to normal in the high-dose group and were maintained well below the levels in vehicle-treated mice throughout the study.
4.Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2.
Purandare AV1, 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, Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21.
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.
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