title: Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors.
abstract: The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Peng
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Tu
authors.forename: Pang-Min
authors.initials: PM
authors.lastname: Liu
authors.forename: John Tsu-An
authors.initials: JT
authors.lastname: Hsu
authors.forename: Prashanth Kumar
authors.initials: PK
authors.lastname: Amancha
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: Sing-Yi
authors.initials: SY
authors.lastname: Wang
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Hsu-Yi
authors.initials: HY
authors.lastname: Sun
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Ping-Chiang
authors.initials: PC
authors.lastname: Lyu
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: C553185:DFG peptide; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors