title: Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments.
abstract: The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phenylaminopyrimidine (PAP) and unsymmetrically disubstituted urea as two fragments that are frequently presented in FDA-approved protein kinase inhibitors. We therefore defined PAP and unsymmetrically disubstituted urea as privileged fragments for kinase drug discovery. A pharmacophore for type II inhibitors, 4-phenylaminopyrimidine urea (4-PAPU), was assembled based upon these privileged fragments. Lead compound SI-046 with BRAF V600E inhibitory activity comparable to the template compound sorafenib was in turn obtained through preliminary structure-activity relationship (SAR) study. Molecular docking suggested that SI-046 is a bona fide type II kinase inhibitor binding to the structurally validated "classical DFG-out" conformation of BRAF V600E. Our privileged fragments-based approach was shown to efficiently deliver a bona fide type II kinase inhibitor lead. In essence, the theme of this article is to showcase the strategy and rationale of our approach.
authors.affiliation: Division of Medicinal Chemistry, Shanghai Institute of Pharmaceutical Industry, 285 Gebaini Road, Pudong, Shanghai 201203, China. chembiomed@163.com.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Lead Compound Research, WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Pilot Free Trade Zone, Pudong, Shanghai 200131, China. cherryjin1031@gmail.com.
authors.forename: Xuejin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjia Xiang, Gulou, Nanjing 210009, Jiangsu, China. youqd@163.com.
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003062:Codon; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E; classical DFG-out conformation; fragment-based lead discovery; privileged fragments; type II kinase Inhibitor