Allosteric modulators of MEK1: drug design and discovery.
Mitogen-activated protein kinase kinase (MAPKK, MEK) mediates signal transduction, controlling cell proliferation and survival. MEK occupies a key downstream position in the Ras-Raf-MEK-ERK signaling pathway, implying that inhibition of MEK will potently suppress tumor cell growth, with potential applications in cancer therapy. Based on the promising therapeutic effects of MEK modulators, continued efforts have been made in this class. Here, we review the discovery and development of MEK1 allosteric modulators, classifying them into four structural groups. The allosteric mechanisms and recent clinical progress involving these modulators are also reviewed.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Jialin
J
Shang
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Shaoyong
S
Lu
School of Biotechnology and Chemical Engineering, Ningbo Institute of Technology, Zhejiang University, Ningbo, China.
Yongjun
Y
Jiang
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. jian.zhang@sjtu.edu.cn.|Medicinal Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. jian.zhang@sjtu.edu.cn.
Jian
J
Zhang
D000494:Allosteric Regulation; D015195:Drug Design; D055808:Drug Discovery; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
MEK1; allosteric mechanism; allosteric modulators; cancer treatment; signaling pathway