title: Structure-based de novo design of Eya2 phosphatase inhibitors.
abstract: Although Eyes absent protein tyrosine phosphatases proved to be involved in various human cancers by a series of persuasive experimental evidence, only a very few number of small-molecule inhibitors have been reported so far. We have been able to identify 29 novel inhibitors of Eyes absent homologue 2 (Eya2) by means of a structure-based de novo design with the two known inhibitor scaffolds that contain a proper chelating group for the active-site Mg²⁺ ion. Because these newly found inhibitors were screened for having desirable physicochemical properties as a drug candidate and exhibited a moderate inhibitory activity with IC₅₀ values ranging from 6 to 50 μM, they deserve consideration for further investigation to develop new anticancer medicines. Structural features relevant to the stabilization of the identified inhibitors in the active site of Eya2 phosphatase are discussed in detail.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Republic of Korea. hspark@sejong.ac.kr
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.forename: Seong Eon
authors.initials: SE
authors.lastname: Ryu
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008274:Magnesium / Q000737:chemistry*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C106938:EYA2 protein, human; D017027:Protein Tyrosine Phosphatases; D008274:Magnesium