Highly Selective MEK Inhibitors

Chih-Shia      Lee; Nicholas      S. Duesbery

Abstract

The Raf-MEK-ERK signaling pathway promotes cell cycle progression and cell proliferation, and it has been shown to play a key role in tumorigenesis and cancer cell survival. Targeting MEK to inhibit the activity of this survival pathway has been a logical strategy for treating cancers. Several MEK inhibitors have been developed and widely used in laboratories as tools to study the signaling pathway. Despite their promising anti-tumor activity in preclinical studies, MEK inhibitors have failed to generate satisfactory responses in clinical trials. Here we review the history of two categories of highly selective MEK inhibitors: non – ATP-competitive small-molecule inhibitors (PD 098059, U0126, PD 184352 and its derivatives) and biological inhibitors (anthrax lethal toxin and Yersinia outer protein J). This review presents a discussion of the mechanisms of these inhibitors and is intended to provide insights into the potential applications of these inhibitors to cancer studies and treatments.

Keywords: Allosteric inhibition, anthrax lethal toxin (LeTx), ARRY-142886 (AZD6244), MAPK/ERK kinase (MEK), mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase (MKK), PD 184352 (CI-1040), Yersinia outer protein J (YopJ), Raf-MEK-ERK signaling pathway, tumorigenesis, microtubule-associated protein, epidermal growth factor (EGF), phorbol 12-myristate 13-acetate, TPA, threonine, tyrosine, viral oncogene, Xenopus oocytes, somatic mutations, melanomas, protein kinase A (PKA), protein kinase C (PKC), U0126, platelet-derived growth factor (PDGF), colon cancer cell xenograft tumors, tumor biopsies, asthenia, adenocarcinoma, immunostaining, xenograft models, Antineoplastic Drug, lethal factor (LF), proteolysis, Kaposi's sarcoma, neuroblastoma, colorectal adenocarcinoma, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), nuclear factor kappa B (NF-;), adenoviral protease (AVP)