STE7 (also known as MAPKK, MAP2K or MEK) kinases are part of the MAPK signalling cascades. They are activated by phosphorylation by upstream STE11 (MAP3K, MAPKKK) kinases and phosphorylate downstream MAPK kinases. Small molecule pharmacological inhibitors, including negative allosteric modulators, of MEKs are used to disrupt signalling via the RAS-RAF-MEK-ERK pathway that drives proliferation in certain cancers.

* Key recommended reading is highlighted with an asterisk

* Wang C, Wang H, Zheng C, Liu Z, Gao X, Xu F, Niu Y, Zhang L, Xu P. (2021) Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer. Eur J Med Chem, 218: 113386. [PMID:33774345]

1. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

2. Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, Rominger CM, Erskine S, Fisher KE, Yang J et al.. (2011) GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res, 17 (5): 989-1000. [PMID:21245089]

3. Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, Petersen K, Siemeister G, Brittain D, Hillig RC. (2013) Optimization of allosteric MEK inhibitors. Part 1: Venturing into underexplored SAR territories. Bioorg Med Chem Lett, 23 (8): 2384-90. [PMID:23474388]

4. Iverson C, Larson G, Lai C, Yeh LT, Dadson C, Weingarten P, Appleby T, Vo T, Maderna A, Vernier JM et al.. (2009) RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res, 69 (17): 6839-47. [PMID:19706763]

5. Pheneger J, Wallace, E, Marlow, A Hurley B, Lyssikatos J, Bendele AM, Lee PA. (2006) Characterization of ARRY-438162, a Potent MEK Inhibitor in Combination with Methotrexate or Ibuprofen in In Vivo Models of Arthritis.[abstract]. American College of Rheumatology 2006 Annual Scientific Meeting,: Abstract 794.

6. Rice KD, Aay N, Anand NK, Blazey CM, Bowles OJ, Bussenius J, Costanzo S, Curtis JK, Defina SC, Dubenko L et al.. (2012) Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973). ACS Med Chem Lett, 3 (5): 416-21. [PMID:24900486]

7. Tatake RJ, O'Neill MM, Kennedy CA, Wayne AL, Jakes S, Wu D, Kugler Jr SZ, Kashem MA, Kaplita P, Snow RJ. (2008) Identification of pharmacological inhibitors of the MEK5/ERK5 pathway. Biochem Biophys Res Commun, 377 (1): 120-5. [PMID:18834865]

8. Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. (2011) Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol, 39 (1): 23-31. [PMID:21523318]