title: Identification of type II inhibitors targeting BRAF using privileged pharmacophores.
abstract: V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF.
authors.affiliation: Division of Medicinal Chemistry, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshan North One Road, Hongkou District, Shanghai, 200437, China.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Chen
authors.forename: Yunsong
authors.initials: Y
authors.lastname: He
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
authors.forename: Houyuan
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C000590555:1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-morpholinopyrimidin-4-ylamino)phenyl)urea; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014508:Urea; D048493:Proto-Oncogene Proteins B-raf; C030986:pyrimidine
keywords: drug design; kinase; pharmacophore; type II inhibitor; urea