Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality.
Caspases have been strongly implicated to play an essential role in apoptosis. A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7. The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis. Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-A resolution. In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S(2) subsite, and do not bind in the caspase primary aspartic acid binding pocket (S(1)). These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes. Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.
Lee
D
D
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Long
S A
SA
Adams
J L
JL
Chan
G
G
Vaidya
K S
KS
Francis
T A
TA
Kikly
K
K
Winkler
J D
JD
Sung
C M
CM
Debouck
C
C
Richardson
S
S
Levy
M A
MA
DeWolf
W E
WE
Keller
P M
PM
Tomaszek
T
T
Head
M S
MS
Ryan
M D
MD
Haltiwanger
R C
RC
Liang
P H
PH
Janson
C A
CA
McDevitt
P J
PJ
Johanson
K
K
Concha
N O
NO
Chan
W
W
Abdel-Meguid
S S
SS
Badger
A M
AM
Lark
M W
MW
Nadeau
D P
DP
Suva
L J
LJ
Gowen
M
M
Nuttall
M E
ME
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3; D053179:Caspase 7; D061945:Caspase Inhibitors; D019902:Chondrocytes / Q000187:drug effects; D003094:Collagen / Q000235:genetics; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010003:Osteoarthritis / Q000188:drug therapy; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D007510:Isatin; D003094:Collagen; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D002166:Camptothecin