A novel small-molecule PPI inhibitor targeting integrin αvβ3-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

Doori Park, Chan Won Park, Young Jin Choi, Jingjing Lin, Dong Hyun Seo, Han Sung Kim, Soo Young Lee, In Cheol Kang

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)131-142
Number of pages12
Publication statusPublished - 2016 Aug 1

Bibliographical note

Funding Information:
This study was supported, in part, by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIP) (No. 2013R1A1A2010577 ; No. 2013R1A2A1A05005153 ) and by the Basic Science Research Program through the NRF funded by the Ministry of Education ( NRF-2013R1A1A2010577 ).

Publisher Copyright:
© 2016 Elsevier Ltd.

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Bioengineering
  • Ceramics and Composites
  • Biomaterials
  • Mechanics of Materials


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