Biological Activity of Kobe0065

Kobe0065 is a novel and effective small-molecule compound inhibiting Ras–Raf interaction by SBDD; exhibits potent activity to competitively inhibit the binding of H-Ras·GTP to c-Raf-1 RBD with a Ki value of 46 ± 13 μM.
IC50 value: 46 uM (Ki) [1]
Target: Ras-Raf
These two compounds(Kobe0065 and Kobe2602), added to the culture medium at 2 and 20 μM, effectively reduced the amount of c-Raf-1 associated with H-Ras G12V in NIH 3T3 cells in a dose-dependent manner, indicating the inhibition of the cellular activity of Ras. A rough estimate of the IC50 value for the cellular Ras–Raf-binding inhibition was around 10 μM (Fig. 1B), which was not much different from the Ki values for the in vitro Ras–Raf-binding inhibition considering thequite low cellular concentration of Raf. A similar inhibitory effect was also observed with NIH 3T3 cells overexpressing K-Ras G12V. Both Kobe0065 and Kobe2602 at 20 μM efficiently inhibited the phosphorylation of MEK and ERK, downstream kinases of Raf in NIH 3T3 cells transiently expressing
H-Ras G12V, although the effect was slightly weaker than that of
2 μM sorafenib.

References on Kobe0065

[1]. Shima, Fumi, et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proceedings of the National Academy of Sciences of the United States of America (2013), 110(20), 8182-8187, S8182/1-S8182/10.