Effect Of Ly2228820

INTRODUCTION

MAPK (mitogen activated protein kinase) inhibitors play vital role in tumor cell growth by blocking the function of various important kinases of cell cycle. LY2228820 is novel compound and an important kinase inhibitor. This compound specifically targets p38?MAPK and p38?MAPK in low concentrations while p38 MAPK and p38 MAPK are targeted at higher concentrations of LY2228820.

Lenalidomide is found to be very promising in treatment of multiple myeloma, LY2228820 is almost have the same function. Different signaling pathways like JNK (Jun N-terminal kinase, NF-?B (nuclear factor ?B) and MAPK (mitogen activated protein kinase) p38 are involved in the disintegration of bone cells within stromal cells. The all of these pathways are stimulated by strong interactions of stromal cells of bone marrow and MM (multiple myeloma cells [1]. They control the total amount of bone tissues by enhancing the bone resorption. Sequestosome-1 (p62) is an adapter protein which play important role in the formation of different intermediates of signaling pathways. However no intrinsic enzymatic action of this protein is reported. A good number of research groups are working to find out the vital functions of p62 that may be utilized to design novel drugs discovery in order to treat multiple myeloma. By targeting this single protein one can check the certain pathways in the microenvironment of MM cells. This mechanism is important in order to arrest the growth and proliferation of osteoclasts and multiple myeloma cells.

The signaling pathways through p38 MAPK and NF-?B were reported as to be activated in stromal cells from multiple myeloma cells patients. When interleukin 6 (IL-6) is high in the cells the signaling pathway of p38 MAPK is activated [1]. The compound which inhibits the p38 MAPK can ultimately reduce the stromal cell p62 levels. This in a result reduces VCAM-I and IL-6 levels in the cell. And because of lower IL-6 levels in stromal cells, myeloma cell growth fails leading to death of MM cells.

Bortezomib is a protease inhibitor and used as a therapeutic drug. These inhibitors hinder the action of different proteosomes, the cellular complexes involve in the breakdown of proteins such as p53 protein in tumor and cancer cells. The administration of LY2228820 alone was able to cytotoxic effects in MM (multiple myeloma) cells but this toxicity was not very high. Various experiments were done in order to understand this mechanism of action. It was found that a heat shock (Hsp-27) phosphorylation was downregulated which is induced by bortezomib and this Hsp-27 is present at downstream target of p38 MAPK [2]. Although the there was no alteration in gene expression of Hsp-27. The Hsp-27 and MAPKAPK2 phosphorylation is induced by TNF-?. LY2228820 also inhibits this TNF-?. As a result a short fall of interleukin-6 level is observed [2]. Certain cytokines such as M-CSF and TNF-? are inhibited by the LY2228820 as shown in different cytokine protein array experiment in positive CD14 cells [2]. The basic principle function of osteoclast formation is the phosphorylation of Hsp-27 induced by sRANKL. This critical step is found to be stopped by LY2228820 [2]. Some of the research groups have also reported that DNA-alkylating agents activity is enhanced by using p38 MAPK inhibitors. These studies were carried out in human glioblastoma xenografts U87MG [3]. LY2228820 can also administer by some other anti-cancer agents such as BIBW2992, Adriamycin and Doxorubicin.

CONCLUSION

In a nut shell LY2228820 an effective anti-cancer kinase inhibitor. This small compound is designed to block the activity of different MAP kinases especially p38. Multiple studies have shown the effect of this molecule on the formation of bone cells as well as inhibition of multiple myeloma cells.

REFERENCES

1. Hiruma1 Y, Honjo T, et al. Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation. Blood 2009 May 14; 113(20) 4894-4902.

2. Ishitsuka K, Hideshima T, et al. 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.

3. Starling J, Campbell R, et al. P38 MAPK inhibitor, LY2228820, causes significant chemopotentiation of temozolomide in U87MG human glioblastoma xenografts. Proc Amer Assoc Cancer Res 2006; 47.

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