CI-1040 - CAS 212631-79-3
Catalog number:
212631-79-3
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
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Targets:
MEK
Description:
CI-1040 is a MEK inhibitor, which demonstrated in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated.
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Synonyms:
CI-1040; PD184352
MSDS:
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Current Developer:
Pfizer
1.Cost-effectiveness analysis of adding pharmacists to primary care teams to reduce cardiovascular risk in patients with Type 2 diabetes: results from a randomized controlled trial.
Simpson SH1, Lier DA2, Majumdar SR1,2,3, Tsuyuki RT3, Lewanczuk RZ3, Spooner R3, Johnson JA2,4. Diabet Med. 2015 Jul;32(7):899-906. doi: 10.1111/dme.12692. Epub 2015 Feb 2.
BACKGROUND: Adding pharmacists to primary care teams significantly improved blood pressure control and reduced predicted 10-year cardiovascular risk in patients with Type 2 diabetes. This pre-specified sub-study evaluated the economic implications of this cardiovascular risk reduction strategy.
2.Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.
Pei XY1, Dai Y1, Felthousen J1, Chen S1, Takabatake Y1, Zhou L1, Youssefian LE1, Sanderson MW1, Bodie WW1, Kramer LB1, Orlowski RZ2, Grant S3. PLoS One. 2014 Mar 4;9(3):e89064. doi: 10.1371/journal.pone.0089064. eCollection 2014.
The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance.
3.HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways.
Wang HY1, Yang SL2, Liang HF3, Li CH4. Int J Mol Sci. 2014 Feb 26;15(3):3507-18. doi: 10.3390/ijms15033507.
Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro.
4.NR4A1 promotes PDGF-BB-induced cell colony formation in soft agar.
Eger G1, Papadopoulos N1, Lennartsson J1, Heldin CH1. PLoS One. 2014 Sep 30;9(9):e109047. doi: 10.1371/journal.pone.0109047. eCollection 2014.
The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG.
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CAS 212631-79-3 CI-1040

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