CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity.
Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAF(V600E) (K(d) BRAF(V600E) = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal-regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC(50) = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAF(V600E) versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10-55 mg/kg) of both pMEK and pERK in BRAF(V600E) colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30-100 mg/kg twice daily) against BRAF(V600E) melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development.
Ambit Biosciences Corporation, San Diego, CA 92121, USA. jjames@ambitbio.com
Joyce
J
James
Bruce
B
Ruggeri
Robert C
RC
Armstrong
Martin W
MW
Rowbottom
Susan
S
Jones-Bolin
Ruwanthi N
RN
Gunawardane
Pawel
P
Dobrzanski
Michael F
MF
Gardner
Hugh
H
Zhao
Merryl D
MD
Cramer
Kathryn
K
Hunter
Ronald R
RR
Nepomuceno
Mangeng
M
Cheng
Dana
D
Gitnick
Mehran
M
Yazdanian
Darren E
DE
Insko
Mark A
MA
Ator
Julius L
JL
Apuy
Raffaella
R
Faraoni
Bruce D
BD
Dorsey
Michael
M
Williams
Shripad S
SS
Bhagwat
Mark W
MW
Holladay
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011799:Quinazolines; C575620:agerafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf