title: Structure-based approach for the discovery of bis-benzamidines as novel inhibitors of matriptase.
abstract: Matriptase, a trypsin-like serine protease, which may be involved in tissue remodeling, cancer invasion, and metastasis. Potent and selective matriptase inhibitors not only would be useful pharmacological tools for further elucidation of the role of matriptase in these processes but also could have therapeutic potential for the treatment and/or prevention of cancers. We report herein the structure-based approach for the discovery of bis-benzamidines as a novel class of potent matriptase inhibitors. The lead compound, hexamidine (1), inhibits not only the proteolytic activity of matriptase, (K(i) = 924 nM) but also of thrombin K(i) = 224 nM). By testing several available analogues, we identified a new analogue (7) that has a K(i) = 208 nM against matriptase and has only weak inhibitory activity against thrombin (K(i) = 2670 nM), thus displaying a 13-fold selectivity toward matriptase. Our results demonstrated that structure-based database screening is effective in the discovery of matriptase inhibitors and that bis-benzamidines represent a class of promising matriptase inhibitors that can be used for further drug design studies. Finally, our study suggested that there is sufficient structural differences between matriptase and its closely related serine proteases, such as thrombin, for the design of potent and selective matriptase inhibitors.
authors: Structural Biology and Cancer Drug Discovery Program, Lombardi Cancer Center, and Department of Oncology, Georgetown University Medical Center, 3900 Reservoir Road, Washington DC 20007, USA.
authors: I J
authors: IJ
authors: Enyedy
authors: S L
authors: SL
authors: Lee
authors: A H
authors: AH
authors: Kuo
authors: R B
authors: RB
authors: Dickson
authors: C Y
authors: CY
authors: Lin
authors: S
authors: S
authors: Wang
mesh_terms: D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D016208:Databases, Factual; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry; D014357:Trypsin / Q000378:metabolism*
chemical_list: D001550:Benzamidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase; D014357:Trypsin; D013917:Thrombin