. MEK inhibitors differ from most of the other currently available kinase inhibitors, in that they do not compete with ATP binding and therefore are endowed with an unusually PXD101 HDAC inhibitor high specificity towards their target, indeed, none of these compounds significantly inhibit the activity of a large panel of protein kinases that include ERK1, JNK1 and p38 MAP kinases in an in vitro assay. Recently, crystal structures of MEK 1 and 2 have been determined as ternary complexes with Mg ATP and PD184352 like inhibitors, showing that both enzymes have a unique inhibitor binding site located in an interior hydrophobic pocket adjacent to, but not overlapping with, the Mg ATP binding site. Binding of MEK inhibitors to this hydrophobic pocket induces several conformational changes in unphosphorylated MEK, locking them into a closed and catalytically inactive conformation.
Notably, the MEK inhibitor binding site is located in a region where the sequence homology to other protein kinases is quite PHA-739358 827318-97-8 low. With the exception of MEK 2 and MKK 5, all other protein kinases share low sequence identity with MEK 1 in the inhibitor binding site, thereby explaining why PD184352 like MEK inhibitors are exceptionally specific for MEK 1, MEK 2, and MKK 5, but do not inhibit many other protein kinases. First generation MEK inhibitors, such as PD98059 and U0126, have been extremely useful in vitro for establishing the role of the MEK/ERK module in a variety of biological processes. However, their unfavourable pharmacologic characteristics have largely precluded in vivo use and clinical testing.
CI 1040 was the first MEK inhibitor reported to inhibit tumour growth in vivo and, based on its anti tumour activity in a variety of preclinical models of human cancer, was subsequently moved into clinical trials in patients with advanced solid tumours. In phase I and II studies of CI 1040, 77 and 67 patients with a variety of solid tumours were treated, respectively. Treatment was generally well tolerated and phosphorylated ERK levels, measured in tumour samples by quantitative immunohistochemistry, were found to be inhibited by an average of 71%, indicating promising on target activity. However, the metabolic stability, bioavailability, and clinical activity were considered insufficient to warrant further development in the tumour types tested and development of CI 1040 was terminated in favour of developing more potent and biopharmaceutically superior compounds.
Two novel, orally bioavailable, MEK inhibitors endowed with increased potency against MEK and superior biopharmaceutical properties have recently been described. Both compounds have shown promising preclinical activity in vitro and in vivo against a broad spectrum of solid tumours and haematological malignancies and are currently in Phase I/II clinical testing. While effective suppression of ERK phosphorylation in either paired tumour biopsies or peripheral blood mononuclear cells has been demonstrated with both compounds, objective responses have been so far reported only with PD0325901. 4.2. Molecular determinants of sensitivity/resistance to MEK inhibitors The challenges we face in the design and interpretation of clinical trials of MEK inhibitors do not differ substantially from those faced with other anticancer agents, particularly signaltransduction inhibitors. Indeed, we do not presently know which tumour types will be most sensitive or which molecular alterations of the target or pathway are common to patients who be