LY2228820 - CAS 862505-00-8
Catalog number: 862505-00-8
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Description:
LY2228820 is a novel and potent p38MAPK inhibitor (the IC50 for p38αMAPK and p38βMAPK were 7 nM and 3 nM, respectively).
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Purity:
>98%
Appearance:
White to off-white solid
Synonyms:
Ralimetinib
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Current Developer:
Eli Lilly.
1.LY2228820 dimesylate, a selective inhibitor of p38 mitogen-activated protein kinase, reduces angiogenic endothelial cord formation in vitro and in vivo.
Tate CM1, Blosser W, Wyss L, Evans G, Xue Q, Pan Y, Stancato L. J Biol Chem. 2013 Mar 1;288(9):6743-53. doi: 10.1074/jbc.M112.425553. Epub 2013 Jan 18.
LY2228820 dimesylate is a highly selective small molecule inhibitor of p38α and p38β mitogen-activated protein kinases (MAPKs) that is currently under clinical investigation for human malignancies. p38 MAPK is implicated in a wide range of biological processes, in particular those that support tumorigenesis. One such process, angiogenesis, is required for tumor growth and metastasis, and many new cancer therapies are therefore directed against the tumor vasculature. Using an in vitro co-culture endothelial cord formation assay, a surrogate of angiogenesis, we investigated the role of p38 MAPK in growth factor- and tumor-driven angiogenesis using LY2228820 dimesylate treatment and by shRNA gene knockdown. p38 MAPK was activated in endothelial cells upon growth factor stimulation, with inhibition by LY2228820 dimesylate treatment causing a significant decrease in VEGF-, bFGF-, EGF-, and IL-6-induced endothelial cord formation and an even more dramatic decrease in tumor-driven cord formation.
2.P38 regulates the Wnt inhibitor Dickkopf-1 in breast cancer.
Rachner TD1, Göbel A2, Browne A2, Hötzel J2, Rauner M2, Hofbauer LC3. Biochem Biophys Res Commun. 2015 Oct 30;466(4):728-32. doi: 10.1016/j.bbrc.2015.09.101. Epub 2015 Sep 25.
Dickkopf-1 (DKK-1) is an inhibitor of canonical Wnt signalling and has been associated with the progression of osteolytic bone metastases by impairing osteoblast activity. In addition, there is growing evidence supporting a direct anti-tumour effect of DKK-1. The p38 mitogen-activated protein kinase (MAPK) regulates intracellular responses that have been linked to cell cycle, apoptosis and tumorigenesis. P38 inhibitors are currently under clinical evaluation for the treatment of malignancies. However, the influence of p38 on DKK-1 in breast cancer remains elusive. In this work, we show that p38 inhibition using SB202190 or LY2228820 potently suppressed DKK-1 expression by MDA-231 and MCF-7 breast cancer cell lines as well melanoma derived MDA-435 cells. Vice versa, activation of p38 signalling by anisomycin induced DKK-1 expression. Immunohistochemical analysis of DKK-1 expression in 97 breast cancer samples revealed that high expression of p38 was associated with a higher expression of DKK-1 compared to tumours with low p38 expression.
3.A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer.
Patnaik A1, Haluska P2, Tolcher AW1, Erlichman C2, Papadopoulos KP1, Lensing JL2, Beeram M1, Molina JR2, Rasco DW1, Arcos RR1, Kelly CS3, Wijayawardana SR4, Zhang X4, Stancato LF4, Bell R4, Shi P4, Kulanthaivel P4, Pitou C5, Mulle LB6, Farrington DL4, Cha Clin Cancer Res. 2016 Mar 1;22(5):1095-102. doi: 10.1158/1078-0432.CCR-15-1718. Epub 2015 Nov 18.
PURPOSE: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.
4.Understanding Disease-Drug Interactions in Cancer Patients: Implications for Dosing Within the Therapeutic Window.
Coutant DE1, Kulanthaivel P1, Turner PK2, Bell RL2, Baldwin J2, Wijayawardana SR3, Pitou C2, Hall SD1. Clin Pharmacol Ther. 2015 Jul;98(1):76-86. doi: 10.1002/cpt.128. Epub 2015 May 19.
The human inflammatory response can result in the alteration of drug clearance through effects on metabolizing enzymes or transporters. In this article we briefly review the theory of how cancer can lead to indirect changes in drug metabolism, review acute phase proteins and cytokines as markers of changes in cytochrome P450 (CYP) activity in cancer patients, and provide clinical case examples of how the inflammation in advanced cancer patients can lead to altered CYP-mediated drug clearance.
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CAS 862505-00-8 LY2228820

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