Description
Encorafenib (LGX818) is a new-generation BRAF inhibitor that is under evaluation in clinical trials. However, the underlying mechanism remains to be elucidated. Here we show that LGX818 potently decreased ERK phosphorylation and inhibited proliferation in BRAFV600E melanoma cell lines. Moreover, LGX818 downregulated CyclinD1 in a glycogen synthase kinase 3β-independent manner and induced cell cycle arrest in the G1 phase.
Uses
LGX 818 is potent and selective BRAFV600E kinase inhibitor and can be used for the treatment of proliferative diseases such as solid tumor diseases.
General Description
Class: dual threonine/tyrosine kinase;
Treatment: melanoma with BRAFV600E/K; Oral bioavailability = 85%;
Elimination half-life = 6 h;
Protein binding = 86%
Biological Activity
Encorafenib (LGX818) is a highly potent RAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing B-RAF(V600E) with EC50 of 4 nM. Phase 3.
Pharmacokinetics
Encorafenib shows an oral bioavailability of 85%
and a half-life of 6 h. It is administered orally once a
day (450 mg), whereas the other two dabrafenib and
vemurafenib are taken twice a day (Table 2, Section
10.1). The primary metabolic pathway is
N-dealkylation, with CYP3A4 as the main contributor
(Fig. 1).
Clinical Use
Encorafenib (LGX818) is a new-generation BRAF inhibitor. It is currently under investigation in clinical trials for the treatment of BRAF mutant metastatic melanoma patients . LGX818 induces sustained mitogen-activated protein kinase (MAPK) pathway inhibition and has selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E. However, the mechanism by which LGX818 suppresses BRAF mutant melanoma cell proliferation has not been thoroughly investigated.
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.
[2] huang t, karsy m, zhuge j, et al. b-raf and the inhibitors: from bench to bedside. j hematol oncol, 2013, 6(1): 30.
