A small molecule mitigates hearing loss in a mouse model of Usher syndrome III

Nat Chem Biol. 2016 Jun;12(6):444-51. doi: 10.1038/nchembio.2069. Epub 2016 Apr 25.

Abstract

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

MeSH terms

  • Animals
  • Disease Models, Animal*
  • High-Throughput Screening Assays
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Pyridazines / therapeutic use
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Structure-Activity Relationship
  • Usher Syndromes / drug therapy*
  • Usher Syndromes / genetics

Substances

  • BF844 compound
  • CLRN1 protein, human
  • Clrn1 protein, mouse
  • Membrane Proteins
  • Pyrazoles
  • Pyridazines
  • Small Molecule Libraries

Associated data

  • PubChem-Substance/312698285
  • PubChem-Substance/312698286
  • PubChem-Substance/312698287
  • PubChem-Substance/312698288
  • PubChem-Substance/312698289
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  • PubChem-Substance/312698295
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  • PubChem-Substance/312698298
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  • PubChem-Substance/312698306
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  • PubChem-Substance/312698316