2. Academic Validation
  3. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4

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

  • Bioorg Med Chem Lett. 2014 Jul 1;24(13):2885-91. doi: 10.1016/j.bmcl.2014.04.089.
Yingcai Wang 1,  Richard Connors 2,  Pingchen Fan 2,  Xiaodong Wang 2,  Zhongyu Wang 2,  Jiwen Liu 2,  Frank Kayser 2,  Julio C Medina 2,  Sheree Johnstone 2,  Haoda Xu 2,  Stephen Thibault 2,  Nigel Walker 2,  Marion Conn 3,  Ying Zhang 3,  Qingxiang Liu 3,  Mark P Grillo 4,  Alykhan Motani 3,  Peter Coward 3,  Zhulun Wang 5
Affiliations

Affiliations

  • 1 Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: [email protected].
  • 2 Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
  • 3 Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
  • 4 Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
  • 5 Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 24835984 DOI: 10.1016/j.bmcl.2014.04.089
Abstract

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.

Keywords

A1120; Fenretinide; Non-retinoid; RBP4; Small molecules.

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