title: A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice.
abstract: Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin αvβ3-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silico structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin αvβ3, an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin αvβ3 linked to Pyk2, c-Src, PLCγ2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function.
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Doori
authors.initials: D
authors.lastname: Park
authors.affiliation: BioChip Research Center, Hoseo University, Asan 336-795, South Korea.
authors.forename: Chan-Won
authors.initials: CW
authors.lastname: Park
authors.affiliation: BioChip Research Center, Hoseo University, Asan 336-795, South Korea.
authors.forename: YoungJin
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Biomedical Engineering, Yonsei University, Wonju 220-710, South Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, Yonsei University, Wonju 220-710, South Korea.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, South Korea. Electronic address: leesy@ewha.ac.kr.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: BioChip Research Center, Hoseo University, Asan 336-795, South Korea; Department of Biological Science, College of Natural Science and Hoseo University, Asan 336-795, South Korea; InnoPharmaScreen Inc., Asan 336-795, South Korea. Electronic address: ickang@hoseo.edu.
authors.forename: In-Cheol
authors.initials: IC
authors.lastname: Kang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005260:Female; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008024:Ligands; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism*; D010052:Ovariectomy; D011485:Protein Binding / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects*; D053245:RANK Ligand; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000199:Actins; D039302:Integrin alphaVbeta3; D008024:Ligands; D053245:RANK Ligand; D054852:Small Molecule Libraries; D053495:Osteopontin
keywords: Bone resorption; In silico molecular docking simulation; Integrin α(v)β(3)-OPN interface; Osteoclast inhibition; ProteoChip; Small-molecule PPI inhibitor