Kinase inhibitor: MEK. Limits 'cytokine storm' induced by SARS-CoV and MERS-CoV. Li & De Clercq Nat. Rev. Drug Discov. 19:149, Feb 19 2020 , https://doi.org/10.1038/d41573-020-00016-0; Laise et al. bioRxiv, May 17 2020, https://doi.org/10.1101/2020.05.12.091256.
Biochemicals & reagents
1) Gilmartin 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. 17 989 2) Abe et al. (2011), Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO solvate); ACS Med.Chem.Lett. 2 320 3) Allegrezza et al. (2016), Trametinib Drives T-cell-Dependent Control of KRAS Tumors by Inhibiting Pathological Myelopoiesis; Cancer Res. 76 6253 4) Vella et al. (2014), MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells; Cancer Immunol.Res. 2 351 5) Yamaguchi et al. (2012), Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide; Inflamm.Res. 61 445
Trametinib is a highly potent (IC50 uMEK1 = 0.7 nM, pp-MEK1 = 14.9 nM) (1) and is a selective MEK inhibitor displaying selective inhibition of proliferation in various BRAF mutant cancer cell lines (IC50 ACHN = 9.8 nM; IC50 HT-29 = 0.57 nM) (2). This compound is approved for use against unresectable or metastatic BRAF-mutant melanoma alone or in combination with Dabrafenib. Trametinib can limit outgrowth of tumors without directly inhibiting tumor cell proliferation via abrogation of cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) through a mechanism involving CD8+ T cells.3,4 Trametinib also displays potent anti-arthritic effects.5