MEK INHIBITOR AGAINST SUSTAINED GROWTH OF CELLS

by Selleckchem | Mar 19 2012

Introduction: The RAS-Raf-MEK-MAPK pathway

One of the pathways researched in relation to cancerous properties is that of the RAS-Raf –MEK-MAPK phosphorylation signaling cascade. This pathway has been linked with the regulation of gene transcription via the nucleus receptor MAPK. The pathway is initiated via transmembrane receptor proteins such as EDGR, VEGFR, PDGFR or IGFR which receives an extracellular signal via ligand binding which is translated into the phosphorylation of the membrane bound protein RAS via the exchange of GDP for GTP in the complex receptor protein SOS and GRB2. RAS is the description of a family of proteins with a signature binding domain they are located in the intracellular side to the cell membrane [1]. They become activated through phosphorylation and subsequently activate the next protein in the series, Raf. Raf is a series of proteins that are located in the cytosole or the cell membrane depending on their active status, active Raf trans-locates towards the nucleus and its target MEK [2-6]. MEK is a nexus point for this pathway and several others, receiving signals and then passing them to the MAPK protein located in the nucleus. Depending on the source of the signal MAPK then regulate the activity of gene transcription via proteins such as C-myc, MNK and CREB in relation to the progression of the cell cycle. RAS and Raf both have been investigated as targets for inhibition since the RAS to MAPK cascade is frequently found to be over expressed in several forms of cancer . However, both RAS and Raf have important isoforms which appear to be mutated into permanently active structures. This sends the signaling pathway out of control and unregulated cell growth is a direct result. Inhibitors direct at both RAs and Raf are subject to resistance due to non reactive mutations. The theory behind a MEK kinase inhibitor is the fact that MEK has no known mutations to date hence MEK inhibition would be uniform across sensitive and resistant tumor types, it is further downstream from RAS and RAf hence would block signals from the mutated forms as well as the non mutated forms [7].

MEK specific inhibitor

To design a MEK pathway inhibitor requires two basic things knowledge of the mechanism of action for MEK and knowledge of the MEK structure. Since MEK is a serine/Threonine type Tyrosine kinase receptor the direct inhibition of the ADP to ATP exchange was determined to be the best route for inhibitor design. Loosely based on endogenous nucleosides small molecule inhibitors were designed to competitively bind to the ATP domain on the tyrosine kinase protein. Examples of such molecules are trametinib, U0126, selumetinib, CI-1040 or PD035901 which have all been tested to one degree or another in the clinic [2;3;8].

MEK INHIBITORS:

MEK inhibitor drug design seems to focus on the analogues of purine and pyrimidine and several have reached clinical phase testing. However, despite the focused nature of the target molecules designed for the inhibition of MEK mostly seem to be too toxic [9]. The few that do reach clinical testing phases also have some peculiarities associated with them. A MEK selective inhibitor is not really possible with two MEK isoforms existing and the molecules quoted above generally inhibit both forms. Only MEK antagonist have been discovered to date and no MEK agonist have been designed. For research the MEK price to buy MEK inhibitor variable depending on the MEK supplier used, although they are quoted quite often on the biochemical websites.

Clinical Status: MEK Inhibitors

Significantly most MEK inhibitors in clinical trials are at the phase I or II stage after preclinical work established that there was significant anti tumor activity with these molecules. Current trials are mostly in advanced solid tumors or metatstic melanomas and due for completion in two to three years times. Completed trials are being data processed and results are expected sometime in 2012 [10].

References

1. Alvarado Y, Giles FJ. Ras as a therapeutic target in hematologic malignancies. Expert Opin Emerg Drugs 2007; 12(2):271-284.

2. Allen LF, Sebolt-Leopold J et al. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin Oncol 2003; 30(5 Suppl 16):105-116.

3. Trujillo JI. MEK inhibitors: a patent review 2. Expert Opin Ther Pat 2011; 21(7):1045-1069.

4. Gollob JA, Wilhelm S et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 2006; 33(4):392-406.

5. Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis 2010; 31(7):1165-1174.

6. Keller ET, Fu Z et al. The role of Raf kinase inhibitor protein (RKIP) in health and disease. Biochem Pharmacol 2004; 68(6):1049-1053.

7. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway. Recent Pat Anticancer Drug Discov 2009; 4(1):28-35.

8. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des 2002; 8(25):2255-2257.

9. Boschelli DH. 4-anilino-3-quinolinecarbonitriles: an emerging class of kinase inhibitors. Curr Top Med Chem 2002; 2(9):1051-1063.

10. Reig M, Bruix J. Medical treatments: in association or alone, their roles and their future perspectives: the Western experience. J Hepatobiliary Pancreat Sci 2010; 17(4):420-421.

Cat.No.	Product Name	Information
S1102	U0126-EtOH	U0126-EtOH is a highly selective inhibitor of MEK1/2 with IC50 of 0.07 μM/0.06 μM in cell-free assays, 100-fold higher affinity for ΔN3-S218E/S222D MEK than PD98059. U0126 inhibits autophagy and mitophagy with antiviral activity.
S1008	Selumetinib (AZD6244)	Selumetinib (AZD6244, ARRY-142886) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib suppresses cell proliferation, migration and trigger apoptosis. Phase 3.
S1020	PD184352 (CI-1040)	PD184352 (CI-1040) is an ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, 100-fold more selective for MEK1/2 than MEK5. PD184352 (CI-1040) selectively induces apoptosis.
S1036	Mirdametinib (PD0325901)	Mirdametinib (PD0325901) is a selective and non ATP-competitive MEK inhibitor with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. Phase 2.