title: ST101 induces a novel 17 kDa APP cleavage that precludes Aβ generation in vivo.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders, University of California at Irvine, Irvine, CA 92697-4545, USA. kngreen@uci.edu
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Hasan
authors.initials: H
authors.lastname: Khashwji
authors.forename: Tatiana
authors.initials: T
authors.lastname: Estrada
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
mesh_terms: D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008252:Macaca fascicularis; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013141:Spiro Compounds / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D007189:Indans; D010446:Peptide Fragments; D013141:Spiro Compounds; D014404:Tubulin; C543304:amyloid beta-protein precursor C-terminal fragment beta, human; C511224:spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one; D016875:tau Proteins; D002402:Cathepsin D