title: PLX-4032, a small-molecule B-Raf inhibitor for the potential treatment of malignant melanoma.
abstract: PLX-4032 is a small-molecule, orally available B-Raf kinase inhibitor being developed by Plexxikon Inc and Hoffman-La Roche Ltd for the treatment of cancers harboring activating BRAF mutations. The primary focus of development is in melanoma (> 50% harbor activating BRAF mutations) with other solid tumors, such as colorectal carcinoma (> 10% harbor BRAF mutations), also under investigation. Purified kinase assays have demonstrated that PLX-4032 and its related analogs are highly potent inhibitors of B-Raf activity, with 3-fold selectivity for the V600E mutation over the wild-type kinase. In preclinical models, PLX-4032 and its analogs inhibited the growth of BRAFV600E-positive melanoma cell lines both in vitro and in vivo. In phase I clinical trials, PLX-4032 was well tolerated and objective responses were observed in several patients with BRAFV600E-positive tumors. Responses correlated well with inhibition of intratumoral phospho-ERK and cell proliferation, and reductions in fluorodeoxyglucose uptake on PET scanning. A preliminary analysis of this phase I data suggested that progression-free survival was approximately 7 months, and phase II and III clinical trials are now underway. These studies provide the proof-of-concept for B-Raf as a therapeutic target in melanoma.
authors.affiliation: The Moffitt Cancer Center, Programs of Molecular Oncology and Cutaneous Oncology, 12902 Magnolia Drive, Tampa, FL, 33612, USA. keiran.smalley@moffitt.org
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D000818:Animals; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf