Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1.
Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Christina J
CJ
Crump
Benjamin A
BA
Fish
Suita V
SV
Castro
De-Ming
DM
Chau
Natalya
N
Gertsik
Kwangwook
K
Ahn
Cory
C
Stiff
Nikolay
N
Pozdnyakov
Kelly R
KR
Bales
Douglas S
DS
Johnson
Yue-Ming
YM
Li