Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer

Chao Wang; Han Wang; Cangxin Zheng; Zhenming Liu; Xiaozuo Gao; Fengrong Xu; Yan Niu; Liangren Zhang; Ping Xu

doi:10.1016/j.ejmech.2021.113386

Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer

Eur J Med Chem. 2021 Jun 5:218:113386. doi: 10.1016/j.ejmech.2021.113386. Epub 2021 Mar 19.

Authors

Chao Wang¹, Han Wang², Cangxin Zheng², Zhenming Liu³, Xiaozuo Gao⁴, Fengrong Xu², Yan Niu², Liangren Zhang³, Ping Xu⁵

Affiliations

¹ National Pharmaceutical Teaching Laboratory Center, School of Pharmaceutical Sciences, Peking University, Beijing, China.
² Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing, China.
³ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
⁴ Royal Melbourne Institute of Technology University, Melbourne, Australia.
⁵ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing, China. Electronic address: pingxu@bjmu.edu.cn.

PMID: 33774345
DOI: 10.1016/j.ejmech.2021.113386

Abstract

Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) are the crucial part of the RAS-RAF-MEK-ERK pathway (or ERK pathway), which is involved in the regulation of various cellular processes including proliferation, survival, and differentiation et al. Targeting MEK has become an important strategy for cancer therapy, and 4 MEK inhibitors (MEKis) have been approved by FDA to date. However, the application of MEKis is limited due to acquired resistance under long-term treatment. Fortunately, an emerging technology, named proteolysis targeting chimera (PROTAC), could break through this limitation by inducing MEK1/2 degradation. Compared to MEKis, MEK1/2 PROTAC is rarely studied and only three MEK1/2 PROTAC molecules, have been reported until now. This paper will outline the ERK pathway and the mechanism and research progress of MEK1/2 inhibitors, but focus on the development of MEK degraders and their optimization strategies. PAC-1 strategy which can induce MEK degradation indirectly, other PROTACs on ERK pathway, the advantages and challenges of PROTAC technology will be subsequently discussed.

Keywords: Degrader; Inhibitor; MEK; PROTAC.

Publication types

Review

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Dose-Response Relationship, Drug
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors*
MAP Kinase Kinase 1 / metabolism
MAP Kinase Kinase 2 / antagonists & inhibitors*
MAP Kinase Kinase 2 / metabolism
Molecular Structure
Neoplasms / drug therapy*
Neoplasms / metabolism
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
MAP2K2 protein, human
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human