1. Academic Validation
  2. 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: yingcai02@gmail.com.
  • 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: zwang@amgen.com.
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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