Kim N Green1, Hasan Khashwji, Tatiana Estrada, Frank M Laferla. 1. 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
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.
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.
Authors: David Baglietto-Vargas; Rodrigo Medeiros; Hilda Martinez-Coria; Frank M LaFerla; Kim N Green Journal: Biol Psychiatry Date: 2013-01-08 Impact factor: 13.382
Authors: Monica R P Elmore; Allison R Najafi; Maya A Koike; Nabil N Dagher; Elizabeth E Spangenberg; Rachel A Rice; Masashi Kitazawa; Bernice Matusow; Hoa Nguyen; Brian L West; Kim N Green Journal: Neuron Date: 2014-04-16 Impact factor: 17.173
Authors: H N Banerjee; G Hyman; S Evans; V Manglik; E Gwebu; A Banerjee; D Vaughan; J Medley; C Krauss; J Wilkins; V Smith; A Banerji; J Rousch Journal: J Membr Sci Technol Date: 2014-02-15
Authors: Stefania Forner; Shimako Kawauchi; Gabriela Balderrama-Gutierrez; Enikö A Kramár; Dina P Matheos; Jimmy Phan; Dominic I Javonillo; Kristine M Tran; Edna Hingco; Celia da Cunha; Narges Rezaie; Joshua A Alcantara; David Baglietto-Vargas; Camden Jansen; Jonathan Neumann; Marcelo A Wood; Grant R MacGregor; Ali Mortazavi; Andrea J Tenner; Frank M LaFerla; Kim N Green Journal: Sci Data Date: 2021-10-15 Impact factor: 6.444
Authors: Dominic I Javonillo; Kristine M Tran; Jimmy Phan; Edna Hingco; Enikö A Kramár; Celia da Cunha; Stefania Forner; Shimako Kawauchi; Giedre Milinkeviciute; Angela Gomez-Arboledas; Jonathan Neumann; Crystal E Banh; Michelle Huynh; Dina P Matheos; Narges Rezaie; Joshua A Alcantara; Ali Mortazavi; Marcelo A Wood; Andrea J Tenner; Grant R MacGregor; Kim N Green; Frank M LaFerla Journal: Front Neurosci Date: 2022-01-24 Impact factor: 4.677