The overview of Mitogen-activated extracellular signal-regulated kinase (MEK)-based dual inhibitor in the treatment of cancers. (15th September 2022)

• Record Type: Journal Article
• Authors: Wang, Hao; Chi, Lingling; Yu, Fuqiang; Dai, Hongling; Si, Xiaojie; Gao, Chao; Wang, Zhengjie; Liu, Limin; Zheng, Jiaxin; Ke, Yu; Liu, Hongmin; Zhang, Qiurong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 70(2022)
• Publication Date: 2022-09-15
• Subjects: Dual inhibitor -- MEK -- Anticancer -- Drug resistance -- Rational design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116922
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1/2) are the critical components of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MAPK/ERK1/2) signaling pathway which is one of the well-characterized kinase cascades regulating cell proliferation, differentiation, growth, metabolism, survival and mobility both in normal and cancer cells. The aberrant activation of MAPK/ERK1/2 pathway is a hallmark of numerous human cancers, therefore targeting the components of this pathway to inhibit its dysregulation is a promising strategy for cancer treatment. Enormous efforts have been done in the development of MEK1/2 inhibitors and encouraging advancements have been made, including four inhibitors approved for clinical use. However, due to the multifactorial property of cancer and rapidly arising drug resistance, the clinical efficacy of these MEK1/2 inhibitors as monotherapy are far from ideal. Several alternative strategies have been developed to improve the limited clinical efficacy, including the dual inhibitor which is a single drug molecule able to simultaneously inhibit two targets. In this review, we first introduced the activation and function of the MAPK/ERK1/2 components and discussed the advantages of MEK1/2-based dual inhibitors compared with the single inhibitors and combination therapy in the treatment of cancers. Then, we overviewed the MEK1/2-based dual inhibitors for the treatment of cancers and highlighted the theoretical basis of concurrent inhibition of MEK1/2 and other targets for development of these dual inhibitors. Besides, the status and results of these dual inhibitors in both preclinical and clinical studies were also the focus of this review.