title: Discovery of ADDL--targeting small molecule drugs for Alzheimer's disease.
abstract: Amyloid beta-derived diffusible ligands (ADDLs) comprise the neurotoxic subset of soluble Abeta(1-42) oligomers, now widely considered to be the molecular cause of memory malfunction and neurodegeneration in Alzheimer's disease (AD). We have developed a screening cascade which identifies small molecule modulators of ADDL-mediated neurotoxicity. The primary screen involves a fluorescence resonance energy transfer (FRET)-based assay which selects inhibitors of Abeta1-42 oligomer assembly. The identified hits were further characterized by assessing their ability to inhibit the assembly and binding of ADDLs to cultures of primary hippocampal neurons. This approach has led to the identification of a number of small molecules which inhibit ADDL assembly and their subsequent binding to neurons. Here we describe our small molecule discovery efforts to identify ADDL assembly blocker and ADDL binding inhibitors, and to transform validated hits into pre-clinical lead compounds.
authors.affiliation: Acumen Pharmaceuticals, Inc. 385 Oyster Point Blvd., Suite 9A, South San Francisco, CA 94080, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Look
authors.forename: Jasna
authors.initials: J
authors.lastname: Jerecic
authors.forename: Diana B
authors.initials: DB
authors.lastname: Cherbavaz
authors.forename: Todd R
authors.initials: TR
authors.lastname: Pray
authors.forename: Jean-Claude R
authors.initials: JC
authors.lastname: Breach
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Crosier
authors.forename: Lev
authors.initials: L
authors.lastname: Igoudin
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hironaka
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Lowe
authors.forename: Michele
authors.initials: M
authors.lastname: McEntee
authors.forename: Lily
authors.initials: L
authors.lastname: Ruslim-Litrus
authors.forename: Hsiu-Mei
authors.initials: HM
authors.lastname: Wu
authors.forename: Sue
authors.initials: S
authors.lastname: Zhang
authors.forename: Susan M
authors.initials: SM
authors.lastname: Catalano
authors.forename: William F
authors.initials: WF
authors.lastname: Goure
authors.forename: David
authors.initials: D
authors.lastname: Summa
authors.forename: Grant A
authors.initials: GA
authors.lastname: Krafft
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D054852:Small Molecule Libraries
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D054852:Small Molecule Libraries