The mitogen-activated protein kinase (MAPK) signal transduction pathways control key cellular processes such as growth, differentiation, and proliferation, and provide a means for transmission of signals from the cell surface to the nucleus. As a part of the RAS-RAF-MEK-MAPK pathway, MEK (MAP kinase kinase) phosphorylates the MAPK proteins ERK1 and ERK2 (extracellular signal-regulated kinases) as a means for intracellular signaling (Sebolt-Leopold, 2000). Although MEK has not been identified as having oncogenic properties, this kinase serves as a focal point in the signal transduction pathway of known oncogenes (e.g., RAS and RAF) (Mansour et al., 1994). MEK exists downstream of various receptor tyrosine kinases (such as the epidermal growth factor receptor) which have been demonstrated to be important in neoplasia (Jost et al., 2001). RAS activation occurs first, followed by recruitment of RAF (A- RAF, B- RAF, or RAF- 1) proteins to the cell membrane through binding to RAS, with subsequent activation of RAF. RAF phos-phorylates MEK1 and MEK2 on multiple serine residues in the activation
Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy, Edited by Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari Copyright © 2010 John Wiley & Sons, Inc.
process. MEK1 and MEK2 phosphorylate tyrosine or threonine residues on ERK proteins in the signal transduction process, with phosphorylated ERK activating various transcription factors (Friday and Adjei, 2008). Aberrant activation of this pathway has been observed in a diverse group of solid tumors, along with leukemia, and is believed to play a key role in tumorigen-esis (Hoshino et al., 1999; Milella et al., 2001).
Based on a significant amount of preclinical data, development of small-molecule inhibitors of MEK appears to be a rational approach for treatment of various malignancies (Sebolt-Leopold et al., 1999; Dent and Grant, 2001). The first MEK inhibitor to enter clinical trials was CI-1040 (also known as PD0184352), which was intended for oral administration. However, the level of antitumor activity in a multicenter phase II study in patients with various solid tumors was not sufficient to warrant further development of this drug (Rinehart et al., 2004- Wang et al., 2007) . CI-1040 exhibited low oral bio-availability and high metabolism, which were primary factors resulting in insufficient plasma drug levels for antitumor activity.
PD0325901 [Figure 1; chemical name of N-((,R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide] is a highly potent and specific non-ATP competitive inhibitor of MEK (K of 1 nM against activated MEK1 and MEK2 in vitro), and demonstrated anticancer activity against a broad spectrum of human tumors in murine models (Sebolt-Leopold et al., 2004). Preclinical studies indicate that PD0325901 has the potential to impair growth of human tumors that rely on the MEK/MAPK pathway for growth and survival. PD0325901 inhibits the phosphorylation of MAPK proteins (ERK1 and ERK2) as a biochemical mechanism of action, and assays were developed to evaluate inhibition of protein phosphorylation in normal and neoplastic tissues (Brown et al., 2007). This compound has greatly improved pharmacologic and pharmaceutical properties compared with CI-1040 (i.e.,
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