LGX818 (Synonyms: LGX818)

Cell lines

Human melanoma A375 (BRAFV600E) cells

Preparation method

The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.

Reacting condition

3 ~ 900 nM

Applications

In human melanoma A375 (BRAFV600E) cells, LGX818 suppressed phospho-ERK (EC50 = 3 nM), thus potently inhibiting cell proliferation (EC50 = 4 nM). Meanwhile, LGX818 did not show any significant inhibition against a panel of 100 kinases (IC50 > 900 nM) as well as proliferation of > 400 cell lines expressing wild-type BRAF. In addition, biochemical assays showed that the dissociation half-life of LGX818 was >24 hrs. Thus, the inhibition effect of LGX818 remained following drug wash-out.

Animal models

BRAF mutant or wild-type human tumor xenograft models

Dosage form

1 ~ 300 mg/kg; p.o.

Applications

At an oral dose as low as 6 mg/kg, LGX818 potently (75%) and continuously (> 24 hrs) decreased phospho-MEK in human melanoma xenograft models (BRAFV600E). In nude mice and rats bearing multiple BRAF mutant human tumors, LGX818 induced tumor regression at the dose as low as 1 mg/kg. Moreover, for BRAF wild-type tumors, LGX818 did not show any activity at the dose up to 300 mg/kg (b.i.d.), with good tolerability and linear increase in exposure.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Stuart D D, Li N, Poon D J, et al. Preclinical profile of LGX818: A potent and selective RAF kinase inhibitor. Cancer Research, 2012, 72(8 Supplement): 3790.