Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione

J Pharmacol Sci. 2015 Dec;129(4):240-3. doi: 10.1016/j.jphs.2015.09.006. Epub 2015 Nov 17.

Abstract

Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.

Keywords: 6-Benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6); Familial amyloid polyneuropathy (FAP); Transthyretin (TTR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid
  • Amyloid Neuropathies, Familial / drug therapy*
  • Amyloid Neuropathies, Familial / genetics*
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Genomic Instability / drug effects*
  • HEK293 Cells
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Hydroxamic Acids / therapeutic use*
  • Isoquinolines / pharmacology*
  • Isoquinolines / therapeutic use*
  • Molecular Targeted Therapy
  • Mutation*
  • Naphthalimides / pharmacology*
  • Naphthalimides / therapeutic use*
  • Polymerization
  • Prealbumin / chemistry*
  • Prealbumin / genetics*
  • Protein Binding
  • Thyroxine

Substances

  • 6-benzoyl-2-hydroxy-1H-benzo(de)isoquinoline-1,3(2H)-dione
  • Amyloid
  • Hydroxamic Acids
  • Isoquinolines
  • Naphthalimides
  • Prealbumin
  • Thyroxine