title: Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E.
abstract: The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
authors.affiliation: Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States. mrowbottom@ambitbio.com
authors.forename: Martin W
authors.initials: MW
authors.lastname: Rowbottom
authors.forename: Raffaella
authors.initials: R
authors.lastname: Faraoni
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.forename: Brian T
authors.initials: BT
authors.lastname: Campbell
authors.forename: Andiliy G
authors.initials: AG
authors.lastname: Lai
authors.forename: Eduardo
authors.initials: E
authors.lastname: Setti
authors.forename: Maiko
authors.initials: M
authors.lastname: Ezawa
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Sprankle
authors.forename: Sunny
authors.initials: S
authors.lastname: Abraham
authors.forename: Lan
authors.initials: L
authors.lastname: Tran
authors.forename: Brian
authors.initials: B
authors.lastname: Struss
authors.forename: Michael
authors.initials: M
authors.lastname: Gibney
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Ruwanthi N
authors.initials: RN
authors.lastname: Gunawardane
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Nepomuceno
authors.forename: Ianina
authors.initials: I
authors.lastname: Valenta
authors.forename: Helen
authors.initials: H
authors.lastname: Hua
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Merryl D
authors.initials: MD
authors.lastname: Cramer
authors.forename: Dana
authors.initials: D
authors.lastname: Gitnick
authors.forename: Darren E
authors.initials: DE
authors.lastname: Insko
authors.forename: Julius L
authors.initials: JL
authors.lastname: Apuy
authors.forename: Susan
authors.initials: S
authors.lastname: Jones-Bolin
authors.forename: Arup K
authors.initials: AK
authors.lastname: Ghose
authors.forename: Torsten
authors.initials: T
authors.lastname: Herbertz
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Bruce
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: Shripad
authors.initials: S
authors.lastname: Bhagwat
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D007555:Isoxazoles; D010671:Phenylurea Compounds; D011799:Quinazolines; C575620:agerafenib; D048493:Proto-Oncogene Proteins B-raf