PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas.
Targeted intervention of the B-Raf V600E gene product that is prominent in melanoma has been met with modest success. Here, we characterize the pharmacological properties of PLX4032, a next-generation inhibitor with exquisite specificity against the V600E oncogene and striking anti-melanoma activity. PLX4032 induces potent cell cycle arrest, inhibits proliferation, and initiates apoptosis exclusively in V600E-positive cells in a variety of in vitro experimental systems; follow-up xenograft studies demonstrate extreme selectivity and efficacy against melanoma tumors bearing the V600E oncoproduct. The collective data support further exploration of PLX4032 as a candidate drug for patients with metastatic melanoma; accordingly, validation of PLX4032 as a therapeutic tool for patients with melanoma is now underway in advanced human (Phase III) clinical trials.
Lee
John T
JT
Department of Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA.
Li
Ling
L
Brafford
Patricia A
PA
van den Eijnden
Marcia
M
Halloran
Molly B
MB
Sproesser
Katrin
K
Haass
Nikolas K
NK
Smalley
Keiran S M
KS
Tsai
James
J
Bollag
Gideon
G
Herlyn
Meenhard
M
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*; D000077484:Vemurafenib
D004791:Enzyme Inhibitors; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf