MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

Abstract

MEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the αC-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition.

Fig. 1. Global cancer statistics for new cases and deaths for 2022 and MEK (%) mutation in different cancers.

Fig. 2. Raf/MEK/ERK or MAPK pathway importance in cell proliferation and survival.

Fig. 3. Structural insight into the MEK protein. (A) MEK linear models and binding pockets. The linear models of MEK1 and MEK2 show the mutations and functional regions. The linear models of both kinases, MEK1 and MEK2, are displayed in relation to their functional domain placements. Above each is a scale with hash marks at the locations of SNPs, somatic cancer mutations, syndrome-related mutations, experimentally discovered phosphorylation sites (blue hash with oval), and predicted phosphorylation sites (blue-green hash). The positions of the amino acids are indicated by numbers starting with the first Met residue. (B) Crystal structure of MEK protein. (C) The majority of MEK protein binding sites. Various binding locations are indicated by different colours. Burgundy, cyan, and blue (C-helix as well as the F-helix binding site). The P-loop/ADP binding site is cornflower blue, while the D-helix binding site is dark green. Green (catalytic loop); yellow and green (activation segment).

Fig. 4. FDA approved MEK inhibitors.

Fig. 5. Clinical trial MEK inhibitor drugs.

Fig. 6. Various synthesized compounds with parent scaffolds as MEK mutant inhibitors.