GW-5074 | c-Raf1 inhibitor

GW-5074 (220904-83-6) is a potent inhibitor of cRAF1 kinase (IC₅₀ = 9 nM).1 Displays 100-fold selectivity for cRAF1 over CDK1, CDK2, c-src, ERK2, MEK, p38, Tie2, VEGFR2 and c-fm. GW-5074 displays neuroprotective effects in vivo via a mechanism that is independent of MEK, ERK, and Akt signaling. GW-5074 was able to reduce mutant huntingtin protein (mHTT) levels but not wild-type via linking mHTT to LC3 leading to autophagic degradation.⁵ A promising new strategy in the field of targeted protein degradation via utilization of autophagy. Cell permeable.

References/Citations:

1) Lackey et al. (2000), The discovery of potent cRaf1 kinase inhibitors; Bioorg. Med. Chem. Lett., 10 223
2) Chang et al. (2005), Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK pathways; Cell Signal., 217 299
3) Huang et al. (2006), Fibroblast growth factor-2 suppresses oridonin-induced L929 apoptosis through extracellular signal-regulated kinase-dependent and phosphatidylinositol 3-kinase-independent pathway; J. Pharmacol. Sci., 102 305
4) Chen et al. (2004), Bradykinin B2 receptor mediates NF-kappaB activation and cyclooxygenase-2 expression via the Ras/Raf-1/ERK pathway in human airway epithelial cells; J. Immunol., 173 5219
5) Li et al. (2019), Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds; Nature, 575 203