The mitogen-activated protein kinase (MAPK) signal pathway plays an important role in cells. It also has a response to many different external stimuli and regulates cellular growth, proliferation.
The Raf isoform B-Raf is one component of this pathway. Besides, it has a high rate of activating mutation in melanoma and other cancers including papillary thyroid, colorectal, et al.
The V600E activating mutation is most common and can increase the basal level activity of the enzyme. Furthermore, the inhibition of mutant B-Raf signaling can lead to the repression of tumor growth. Sorafenib is a potent and orally active Raf inhibitor with IC50s of 6 nM and 20 nM for Raf-1 and B-Raf, respectively. Following, in this article, we will introduce a more potent RAF inhibitor that takes the sorafenib scaffold as a starting point, ML786.
ML786 is an orally bioavailable Raf inhibitor.
ML786 exhibits IC50s of 2.1, 4.2, and 2.5 nM for V600EΔB-Raf, wt B-Raf, and C-Raf, respectively. ML786 also inhibits Abl-1, DDR2, EPHA2, KDR, and RET (IC50=<0.5, 7.0, 11, 6.2, 0.8 nM).
In A375 cells, ML786 inhibits the kinase phosphorylation of ERK with an IC50 of 60 nM.
In a PK study, ML786 possesses excellent physicochemical and PK properties. It exhibits oral bioavailability of 85% and AUC1-24h of 35.9 μM·h in rats with a dose of 10 mg/kg. Furthermore, ML786 exhibits plasma clearance of 0.44 L/h/kg and V of 3.93 L/kg in rats.
In Nude NCR (ν/ν) mice bearing A375 M xenografts, ML786 inhibits the subcutaneous A375 M xenografts in mice. Additionally, after oral administration as a dose of 75 mg/kg, ML786 shows no indication of toxicity or weight loss.
In conclusion, ML786 shows potent inhibition of B-Raf in cells. Besides, it shows excellent PK properties and potently inhibits the B-Raf pathway in mouse PK/PD studies. In vivo, ML786 exhibits good efficacy in B-Raf mutant xenograft studies.
ML786 is a promising Raf inhibitor for cancer research.
Reference:
Gould AE, et, al. J Med Chem. 2011 Mar 24;54(6):1836-46.