Description
In August 2011, the United States FDA approved vemurafenib (PLX-
4032, RO-5185426) for the treatment of patients with metastatic melanoma
with the BRAFV600E mutation. Vemurafenib has been developed as a
targeted therapy for patients with the BRAF gene mutation since oncogenic
B-raf signaling is implicated in approximately 50% of melanomas. Vemurafenib was identified based on an initial high-throughput screen followed by the extensive use of structure-based drug design. Vemurafenib is a potent inhibitor of B-RafV600E kinase (IC
50=13 nM) compared to its potency against wildtype B-raf (IC
50=160 nM) and is fairly selective versus a panel of 200
kinases. It does inhibit other kinases (RAF1, SRMS, ACK1,
MAP4K5, and FGR) and mutant B-raf kinases (BRAFV600K,
BRAFV600D, and BRAFV600R) with enzyme IC
50's of <100 nM.
Chemical Properties
Off-White Solid
Originator
Plexxikon (United States)
Uses
PLX4032 is an orally bioavailable, ATP-competitive inhibitor of mutant V600E and wild type B-Raf kinases (IC50s = 31 and 100 nM, respectively). It inhibits cell proliferation in a variety of cell lines expressing B-Raf V600E and synergizes strongly with taxol, vinblastine, and oxaliplatin in inhibiting the proliferation of B-RafV600E transformed cancer cells. PLX4032 is effective against the growth of tumors bearing the B-Raf V600E mutation.[Cayman Chemical]
Uses
Vemurafenib (PLX4032, RG7204) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM
Uses
Vemurafenib selective BRAFV600E kinase inhibitor; an antitumor agent. Vemurafenib functions by inhibiting the proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAFV600E or other mutant BRAF proteins altered at codon 600.
Definition
ChEBI: A pyrrolopyridine that is 1H-pyrrolo[2,3-b]pyridine which is substituted at position 5 by a p-chlorophenyl group and at positions 3 by a 3-amino-2,6-difluorobenzoyl group, the amino group of which has undergone
ormal condensation with propane-1-sulfonic acid to give the corresponding sulfonamide. An inhibitor of BRAF and other kinases.
Biological Activity
Vemurafenib (PLX4032, RG7204, RO5185426) is a novel and potent inhibitor of B-RafV600E with IC50 of 31 nM in cell-free assay. 10-fold selective for B-RafV600E over wild-type B-Raf in enzymatic assays and the cellular selectivity can exceed 100-fold. Vemurafenib (PLX4032, RG7204) induces autophagy.
in vitro
PLX4032 inhibits B-RAFV600E, C-RAF, as well as wildtype B-RAF, with IC50 of 31 nM, 48 nM and 100 nM, respectively. PLX4032 also inhibits several non-RAF kinases, including ACK1, KHS1, and SRMS, with IC50 of 18 nM to 51 nM. In melanoma cell lines, the inhibitory effect by PLX4032 depends on B-RAF mutational status, because PLX4032 potently inhibits those harboring B-RAF V600 mutants, including V600E, V600D, V600K, and V600R, but not wildtype or other mutants. The IC50 values of PLX4032 on these cells, including MALME-3M, Colo829, Colo38, A375, SK-MEL28, and A2058, ranges from 20 nM to 1 μM. In these cells, PLX4032 (0.1 μM to 30 μM) also inhibits the phosphorylation of both MEK1/2 and ERK1/2. PLX4032 is highly effective in the treatment of melanoma, for its ability of inhibiting B-RAFV600E. However, PLX4032 displays limited effect in colon cancer patients that also carrying B-RAFV600E oncoprotein. The reason for this is that, in colon cancer cells, B-RAFV600E inhibition by PLX4032 results in a rapid feedback EGFR activation, which compensates for the PLX4032-inhibited cell proliferation.
in vivo
In B-RAFV600E-mutant mice xenograft models, PLX4032 (6 mg/kg–20 mg/kg) inhibits tumor growth. In mice xenograft models of LOX, Colo829, and A375 cells, PLX4032 (12.5 mg/kg–100 mg/kg) inhibits tumor growth and prolongs mice survival.
References
[1] VLADIMIR KHAZAK. Selective Raf inhibition in cancer therapy.[J]. Expert Opinion on Therapeutic Targets, 2007, 11 12: 1587-1609. DOI:
10.1517/14728222.11.12.1587[2] WILLIAM D. TAP . Pharmacodynamic Characterization of the Efficacy Signals Due to Selective BRAF Inhibition with PLX4032 in Malignant Melanoma[J]. Neoplasia, 2010, 12 8: Pages 637-649, IN3. DOI:
10.1593/neo.10414[3] JOHN T. LEE. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas[J]. Pigment Cell & Melanoma Research, 2010, 23 6: 820-827. DOI:
10.1111/j.1755-148x.2010.00763.x[4] KEITH T FLAHERTY. Inhibition of mutated, activated BRAF in metastatic melanoma.[J]. New England Journal of Medicine, 2010, 363 9: 809-819. DOI:
10.1056/nejmoa1002011
