Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4

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• 作者：Yingcai Wang^a ; ^{yingcai02@gmail.com" class="auth_mail} ; Richard Connors^a ; Pingchen Fan^a ; Xiaodong Wang^a ; Zhongyu Wang^a ; Jiwen Liu^a ; Frank Kayser^a ; Julio C. Medina^a ; Sheree Johnstone^a ; Haoda Xu^a ; Stephen Thibault^a ; Nigel Walker^a ; Marion Conn^b ; Ying Zhang^b ; Qingxiang Liu^b ; Mark P. Grillo^c ; Alykhan Motani^b ; Peter Coward^b ; Zhulun Wang^a ; ^{zwang@amgen.com" class="auth_mail}
• 关键词：RBP4 ; A1120 ; Non-retinoid ; Small molecules ; Fenretinide
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：1 July 2014
• 年：2014
• 卷：24
• 期：13
• 页码：2885-2891
• 全文大小：4270 K

文摘

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4–TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.