The Inhibition of MEK

MEK (also known as MAPK) is part of a pathway the links the extracellular signals to the nucleus and consists of RAS, a tyrosine kinase protein attached inter-cellularly to the membrane. RAF, a cytosolic protein which shifts to the membrane under the influence of activated RAS, MEK a cytosolic protein that is activated by the action of a phosphorylated RAF, it has a highly  specific activity for ERK ( the last member of the pathway, located in the nucleus and active in gene transcription, cellular growth and cell cycle regulation [1;2]. The interesting fact is the Raf and Erk both can have one of multiple targets but MEK is dedicated to Erk only. This high degree of specificity means that MEK is a prime target for inhibition and the subsequent interference in this pathway. The RAS – ERK pathway has been investigated thoroughly in both normal and tumor tissues where it has been found that in numerous tumor tissues this pathway is over expressed. A specific example is the BRafV600E mutation which can be up to 80% of cases of melanoma [2;3], this mutation activates the pathway to a permanently on situation. Inhibition of the BRaf protein can be achieved but is problematic in that over 30 different mutations have been discovered. Focusing on one mutation means therapeutic treatment might not work on the others, thereby, introducing resistance. However, by inhibiting MEK activation of this pathway can be halted in a single step since MEK has only one target (Erk) .

Inhibition of MEK can be achieved with the AZD6244 MEK inhibitor, preclinical investigations have demonstrated that AZD6244 induces apoptosis in numerous cell lines including cell lines processing the BrafV600E mutation [4]. Treatment of patients with this mutation is recognized as difficult with prognosis being poorer than those patients with wild type BRaf. This fact indicates the potential AZD6244 represents in the treatment of melanoma, prostate, thyroid, colon, and ovarian cancer

AZD6244: Properties and Availability

AZD6244, also known as Selumetinib, is developed by AstraZeneca in co-operation with Array BioPharma. With specificity towards MEK, AZD6244 IC50  has been determined to be 14 nM. The AZD6244 structure is based on the core of a methylbenzimidazole with two substituted side chains. The AZD6244 solubility in water is recorded in the MDSS of Astra Zenica, at pH 1 it is marginally soluble (274 mg/L) but at physiological pH 7.4 AZD6244 is insoluble. To solubilize AZD6244 DMSO is used, although it should be noted that 5-10 µM is the maximum concentration achievable in research buffers. The AZD6244 stability is determined by its storage, AZD6244 is recorded as being photosensitive hence should be stored as a solution and as a solid in amber vials under desiccated conditions. When stored at -20oC the expiration period should be recorded as 2 years after which purity testing should be made. AZD6244 prices range considerable between AZD6244 suppliers, researchers can buy AZD6244 (10 mg vial) for $42 to $397.

AZD6244: Preclinical investigations

Preclinically AZD6244 demonstrated promise in overcoming resistance to treatment in tumors possessing the BRafV600E mutation since it bypasses the mutation by targeting MEK the downstream protein for BRaf. Animal and cell culture testing indicates activity in a variety of tumor types but sensitivity is variable indicating other factors aside from mutation status effect this molecule’s action. With the significant apoptotic effects of AZD6244 in preclinical models its moved to clinical status and phase I and II studies initiated [5-10].

AZD6244: Clinical Status    

AZD6244 clinical trials are numerous and varied across a variety of different diseases showing different responses. Completed trials have indicated that AZD6244 is suited to combination therapy with traditional chemotherapy agents rather than as mono-therapy regime [5-14]. While AZD6244 mono-therapy did not demonstrate improved survival rates compared to the first line treatment used it did not demonstrate a worse profile, prompting continuation of phase II testing. Currently AZD6244 is being trialed in colorectal, melanoma, liver and various other solid tumors types focusing on overcoming resistance in BRaf and KRAS mutated tumors [15].



    1.    Sawe N, Steinberg G et al. Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 2008; 86(8):1659-1669.

    2.    Bettinger BT, Amberg DC. The MEK kinases MEKK4/Ssk2p facilitate complexity in the stress signaling responses of diverse systems. J Cell Biochem 2007; 101(1):34-43.

    3.    Wei F, Yan J et al. Extracellular signal-regulated kinases modulate DNA damage response - a contributing factor to using MEK inhibitors in cancer therapy. Curr Med Chem 2011; 18(35):5476-5482.

    4.    Romano E, Schwartz GK et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol 2011; 12(9):913-922.

    5.    Huynh H. AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma. Cancer 2010; 116(5):1315-1325.

    6.    Yang S, Ngo VC et al. AZD6244 (ARRY-142886) enhances the therapeutic efficacy of sorafenib in mouse models of gastric cancer. Mol Cancer Ther 2009; 8(9):2537-2545.

    7.    Davies BR, Logie A et al. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 2007; 6(8):2209-2219.

    8.    Huynh H, Chow PK et al. AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. Mol Cancer Ther 2007; 6(9):2468-2476.

    9.    Huynh H, Ngo VC et al. AZD6244 enhances the anti-tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 2010; 52(1):79-87.

  10.    Bartholomeusz C, Oishi T et al. MEK 1/2 Inhibitor selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15-dependent Manner in a Mouse Xenograft Model. Mol Cancer Ther 2011.

  11.    Leijen S, Soetekouw PM et al. A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011; 68(6):1619-1628.

  12.    Bodoky G, Timcheva C et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs 2011.

  13.    Bennouna J, Lang I et al. A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs 2011; 29(5):1021-1028.

  14.    Hainsworth JD, Cebotaru CL et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 2010; 5(10):1630-1636.

  15.    De Roock W, De V, V et al. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 2011; 12(6):594-603.

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S1008 Selumetinib (AZD6244) Selumetinib (AZD6244) 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. Phase 3. (419) (14)

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