A novel small-molecule PPI inhibitor targeting integrin α_vβ₃-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

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• 作者：Doori Park^a ; ¹ ; Chan-Won Park^b ; ¹ ; YoungJin Choi^b ; Jingjing Lin^a ; Dong-Hyun Seo^e ; Han-Sung Kim^e ; Soo Young Lee^a ; ^{leesy@ewha.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; In-Cheol Kang^b ; ^c ; ^d ; ^{ickang@hoseo.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Small-molecule PPI inhibitor ; ProteoChip ; In silico molecular docking simulation ; Osteoclast inhibition ; Bone resorption ; Integrin αvβ3-OPN interface
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：98
• 期：Complete
• 页码：131-142
• 全文大小：3313 K

文摘

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 α_vβ₃-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 α_vβ₃, 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 α_vβ₃ 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.