LY2228820

Uses

LY2228820 is a novel and potent p38MAPK inhibitor with potent antiinflammatory activity. LY2228820 significantly inhibited phosphorylation of MAPKAPK2 and/or HSP27, down stream targets of p38MAPK, in both multiple myeloma (MM) cell lines and LT-BMSCs. LY2228820 is a potential candidate to improve MM patient outcome both by enhancing the effect of Bortezomib (B675700) and by reducing osteoskeletal events.

Biological Activity

ly2228820 is a potent, selective, atp-competitive small-molecule inhibitor inhibiting α- and β-isoforms of p38 mapk with ic(50) values of 5.3nm and 3.2 nm, respectively1.in multiple myeloma (mm) cell lines, ly2228820 enhanced the cytotoxicity of bortezomiba via reducing bortezomib-induced phosphorylation of heat shock protein 27 (hsp27). ly2228820 significantly reduced il-6 secretion from bm mononuclear cells (bmmncs) and long term cultured-bm stromal cells (lt-bmscs). besides, ly2228820 can also inhibit secretion of macrophage inflammatory protein-1a (mip-1a) in bmmncs, cd138+ patient mm cells and normal cd14+ osteoclast cells 2.studies in mice implanted with b16-f10 melanoma showed that orally administered ly2228820 can effectively suppress the tumor-phospho-mk2 expression. treatment of ly2228820 caused a significant tumor growth delay in a549 nsclc xenograft models1.

in vivo

target

p38α

IC 50

p38β MAPK: 3.2 nM (IC₅₀); p38α MAPK: 5.3 nM (IC₅₀)

References

1. campbell rm1, anderson bd, brooks na, brooks hb, chan em, de dios a, gilmour r, graff jr, jambrina e, mader m, mccann d, na s, parsons sh, pratt se, shih c, stancato lf, starling jj, tate c, velasco ja, wang y, ye xs.characterization of ly2228820 dimesylate, a potent and selective inhibitor of p38 mapk with antitumor activity. mol cancer ther. 2014 feb;13(2):364-74.2. ishitsuka k1, hideshima t, neri p, vallet s, shiraishi n, okawa y, shen z, raje n, kiziltepe t, ocio em, chauhan d, tassone p, munshi n, campbell rm, dios ad, shih c, starling jj, tamura k, anderson kc. p38 mitogen-activated protein kinase inhibitor ly2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. br j haematol. 2008 may;141(5):598-606.