GW5074 is a potent and selective c-Raf inhibitor (IC50=9nM). GW5074 disrupts cell proliferation and viral replication by inhibiting c-Raf activity and blocking the Ras/Raf/MEK/ERK (MAPK) cascade, while exerting MEK-ERK and Akt-independent neuroprotective effects through Ras/NF-κB-related signaling. GW5074 can be used in research related to tumors, neurodegenerative diseases, and JC polyomavirus (JCPyV) infection[1-4].
In vitro, GW5074 (100μM) treated HCT116 cells and LDHB-knockout HCT116 cells stably expressing HA-LDHBWT/HA-LDHBK329Q for 24h. GW5074 reduced SIRT5 protein levels, increased LDHB acetylation at Lys329, inhibited LDHB enzymatic activity, downregulated autophagy, and induced apoptosis[5]. GW5074 (2μM) combined with all-trans retinoic acid (1μM) treated t(15;17)-negative human myeloblastic leukemia HL-60 cells and two retinoic acid-resistant sublines R38+ and R38- for 48h. GW5074 combined with all-trans retinoic acid enhanced CD11b expression and G1/G0 cell cycle arrest in parental HL-60 cells. In R38- cells, GW5074 upregulated all-trans retinoic acid-induced CD38 expression. In R38+ cells, GW5074 upregulated all-trans retinoic acid-induced CD11b expression and rescued G1/G0 arrest in both resistant cell lines[6].
In vivo, GW5074 (2mg/kg) was intraperitoneally injected into bleomycin (2U/kg; single intranasal instillation)-induced pulmonary fibrosis model C57BL/6 mice, once every 2 days for a total of 7 injections. GW5074 reduced fibronectin expression in mouse lung tissue, decreased collagen deposition and inflammatory cell infiltration, lowered the Ashcroft score for pulmonary fibrosis, and alleviated bleomycin-induced pulmonary fibrosis[7]. GW5074 (0.5mg/kg or 2mg/kg; daily) was intraperitoneally injected into ICR mice exposed to sidestream smoke for 4 weeks (drug administration started after the first week of smoke exposure and lasted for 3 weeks). GW5074 significantly inhibited sidestream smoke-induced airway contractile hyperresponsiveness to carbachol, endothelin-1, and potassium, and attenuated tracheal inflammatory cell infiltration and mucous gland hypertrophy[8].
References:
[1] Chen J, Yu Q, Patterson E, et al. Dinitroaniline Herbicide Resistance and Mechanisms in Weeds. Front Plant Sci. 2021 Mar 25;12:634018.
[2] Singh B, Yun S, Gil Y, et al. The Role of Colchicine in Plant Breeding. Int J Mol Sci. 2025 Jul 14;26(14):6743.
[3] Basit A, Lim KB. Systematic approach of polyploidy as an evolutionary genetic and genomic phenomenon in horticultural crops. Plant Sci. 2024 Nov;348:112236.
[4] Gantait S, Mukherjee E. Induced autopolyploidy-a promising approach for enhanced biosynthesis of plant secondary metabolites: an insight. J Genet Eng Biotechnol. 2021 Jan 8;19(1):4.
[5] Shi L, Yan H, An S, et al. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol Oncol. 2019 Feb;13(2):358-375.
[6] Jensen HA, Bunaciu RP, Varner JD, et al. GW5074 and PP2 kinase inhibitors implicate nontraditional c-Raf and Lyn function as drivers of retinoic acid-induced maturation. Cell Signal. 2015 Aug;27(8):1666-75.
[7] Li S, Liu J, Tan J, et al. Inhibition of Raf1 ameliorates bleomycin-induced pulmonary fibrosis through attenuation of TGF-β1 signaling. Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L241-L247.
[8] Lei Y, Cao YX, Xu CB, et al. The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice. Respir Res. 2008 Nov 3;9(1):71.