subject: Tak-733 Is A Effective Inhibitor Of Mek1/2 [print this page] INTRODUCTION INTRODUCTION
The normal functioning of the cell, its proliferation and apoptosis depend a lot on the Ras activated MAPK pathway. Most of the cancers are due to mutations in this pathway. The hyperactivation of this pathway accompanied by the accumulation of the genetic alterations leads to the transformation of the cell. The cancer cells start showing certain special characters like, being non reactive to antiproliferative signals, inability to enter into the stage of apoptosis, ability to replicate enoromously, continuous angiogenesis etc. There are various factors which lead to this situation but the signal regulated -ERK1/2 pathway plays a major role in this [1][2].
CHEMISTRY OF TAK-733
The chemical name of TAK-733 is 3-[(2R)-2, 3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2, 3-d]pyrimidine-4,7-dione. It is a small molecule which selectively inhibits MEK1/2 and hence acts as a potential antineoplastic agent. Its structure was designed through a bioinformatic technique known as structure-based designing. It has been developed from a new 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione derived compounds which acted like potential MEK1/2 inhibitor. Lead optimization of this series of compounds was done to finally achieve the structure of TAK-733 [3]. TAK-733 is a non competitive inhibitor and it binds to an allosteric site within MEK1/2. Hence it is also known as a non competitive inhibitor of ATP. TAK-733 prevents the phosphorylation of effector proteins which were dependent on MEK1/2 activation. It controls the activity of various transcription factors which in turn regulate the cell signaling which is mediated by the growth factors. MEK1/2 form a vital component of the RAS-RAF-MEK-ERK pathway. These dual specific tyr/thre kinases are upregulated in case of various kinds of tumors.
ORIGIN OF THE STRUCTURE OF TAK-733
TAK-733 has originated from its close structural analogue that is PD0325901. The metabolic instability due to hydroxamate group was rectified while creating this inhibitor. These molecules have pyridopyrimidinedione system in which 2-fluoro-4-iodoaniline portion exhibits the property of a binding motif. This part is also hydrophobic in nature and can get well accommodated into the allosteric site provided by the MEK1/2 inhibitors. This structure has an extra C=O group or the carbonyl group which can form hydrogen bonds with the Val 211 residue and/or Ser212 residue within the allosteric site potentially. This molecule contains a polar side chain which allows supplementary interactions with the residue Lys97. The polar side chain also accounts for the interactions with ATP phosphate. These interactions help this molecule to modulate its physicochemical properties. Substitution by fluorine molecule increases its potency by making it active at a concentration of 3.2nM. This molecule has proved its efficacy in xenograft models of mouse [3].
ACTION OF TAK-733
TAK-733 showed selective inhibition of phosphodiesterases, various kinases (17 in number) at a concentration lesser than 25 M. It also targeted cyclases at a concentration lesser than 10 M. It controlled various mutations in various genes like BRAF, KRAS, PI3K, NRAS, EGFR, MEK1 at a concentration ranging from 2 to 90 nM. TAK-733 also controlled amplification of cMET at the same concentration. It was tested for its efficacy in various xenograft models within human beings. It showed a potential antitumor property [4].
CONCLUSION
In summary TAK-733 is very specific in action towards MEK1/2. It weakens the growth of large number of tumors which depend on the malfunctioning of the MAPK signaling pathway hence proving to be a potential antitumor agent.
REFERENCES
1. Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 2009 Oct 8; 283(2):125-34.
2. Fremin C and Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. Journal of Hematology & Oncology 2010; 3:8.
3. Dong Q, Dougan DR, et al. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg Med Chem Lett 2011 Mar 1; 21(5):1315-9.
4. Shawn M, Tsuchiya S, et al. Abstract 2523: BRAF is not the only predictor of sensitivity in vitro and in vivo for TAK-733, a selective potent inhibitor of MEK1/2. Cancer Res 2010 April 15; 70(8 Supplement): 2523.
