Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
Napper
Andrew D
AD
Elixir Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts 02139, USA. anapper@elixirpharm.com
Hixon
Jeffrey
J
McDonagh
Thomas
T
Keavey
Kenneth
K
Pons
Jean-Francois
JF
Barker
Jonathan
J
Yau
Wei Tsung
WT
Amouzegh
Patricia
P
Flegg
Adam
A
Hamelin
Estelle
E
Thomas
Russell J
RJ
Kates
Michael
M
Jones
Stephen
S
Navia
Manuel A
MA
Saunders
Jeffrey O
JO
DiStefano
Peter S
PS
Curtis
Rory
R
D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D004355:Drug Stability; D005470:Fluorometry; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D009243:NAD / Q000737:chemistry; D009244:NAD+ Nucleosidase / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D011994:Recombinant Proteins; D009243:NAD; D009536:Niacinamide; D009244:NAD+ Nucleosidase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases