ML786 is an Orally Bioavailable Raf Inhibitor

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.

ML786 is an Orally Bioavailable Raf Inhibitor 2020 01 15 - ML786 is an Orally Bioavailable Raf Inhibitor

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.


Gould AE, et, al. J Med Chem. 2011 Mar 24;54(6):1836-46.