Discovery of ADDL--targeting small molecule drugs for Alzheimer's disease.
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.
Look
Gary C
GC
Acumen Pharmaceuticals, Inc. 385 Oyster Point Blvd., Suite 9A, South San Francisco, CA 94080, USA.
Jerecic
Jasna
J
Cherbavaz
Diana B
DB
Pray
Todd R
TR
Breach
Jean-Claude R
JC
Crosier
Walter J
WJ
Igoudin
Lev
L
Hironaka
Catherine M
CM
Lowe
Raymond M
RM
McEntee
Michele
M
Ruslim-Litrus
Lily
L
Wu
Hsiu-Mei
HM
Zhang
Sue
S
Catalano
Susan M
SM
Goure
William F
WF
Summa
David
D
Krafft
Grant A
GA
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
D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D054852:Small Molecule Libraries