ST101 induces a novel 17 kDa APP cleavage that precludes Aβ generation in vivo

Ann Neurol. 2011 May;69(5):831-44. doi: 10.1002/ana.22325. Epub 2011 Mar 17.

Abstract

Objective: Inhibiting Aβ generation is a prime therapeutic goal for preventing or treating Alzheimer disease. Here we sought to identify any disease-modifying properties of an azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-idan]-2(3H)-one (ST101 or ZSET1446).

Methods: The effects of ST101 were studied in 3xTg-AD mice and young cynomolgus monkeys using a combination of biochemical and histological analyses.

Results: Here we describe that ST101 induces cleavage of APP protein at a novel site, generating a 17 kDa C-terminal fragment. This 17 kDa APP cleavage product does not appear to be a substrate for either α- or β-secretase, and thus bypasses generation of Aβ. ST101 is orally active, efficacious at low doses, improves memory function, and robustly reduces brain Aβ in transgenic mice and nonhuman primates.

Interpretation: Using rodent and nonhuman primate models, we show that ST101 represents a novel class of small molecules that reduce central nervous system levels of Aβ by inducing an alternate pathway of APP cleavage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Amyloidogenic Proteins / drug effects*
  • Amyloidogenic Proteins / genetics
  • Amyloidogenic Proteins / metabolism*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Brain / ultrastructure
  • Cathepsin D / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay / methods
  • Humans
  • Indans / pharmacology*
  • Macaca fascicularis
  • Maze Learning / drug effects
  • Memory / drug effects
  • Mice
  • Mice, Transgenic
  • Molecular Weight
  • Neuroblastoma / pathology
  • Peptide Fragments / metabolism
  • Proteomics / methods
  • Reaction Time / drug effects
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism
  • Schizophrenia / pathology
  • Spiro Compounds / pharmacology*
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Transfection
  • Tubulin / metabolism
  • tau Proteins / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Amyloidogenic Proteins
  • Indans
  • Peptide Fragments
  • Spiro Compounds
  • Tubulin
  • amyloid beta-protein precursor C-terminal fragment beta, human
  • spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one
  • tau Proteins
  • Cathepsin D