MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity.
1. Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug-discovery effort, we have synthesized and characterized Z-VD-fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor. 2. MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC50 values ranging from 5 to 20 nm. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC50 values >10 microm). 3. In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide- and tripeptide-based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 microm. 4. MX1013 is more aqueous soluble than tripeptide-based caspase inhibitors such as Z-VAD-fmk. 5. At a dose of 1 mg kg-1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti-Fas mouse-liver apoptosis model, a widely used model of liver failure. 6. At a dose of 20 mg kg-1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury. 7. At a dose of 20 mg kg-1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction. 8. Based on these studies, we conclude that MX1013, a dipeptide pan-caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.
Yang
Wu
W
Cytovia, Inc. (a subsidiary of Maxim Pharmaceuticals, Inc.), 6650 Nancy Ridge Drive, San Diego, CA 92121, U.S.A.
Guastella
John
J
Huang
Jin-Cheng
JC
Wang
Yan
Y
Zhang
Li
L
Xue
Dong
D
Tran
Minhtam
M
Woodward
Richard
R
Kasibhatla
Shailaja
S
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000590:Amino Acid Chloromethyl Ketones / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D014409:Tumor Necrosis Factor-alpha; C484771:benzyloxycarbonyl-valyl-aspartic acid fluoromethyl ketone; C476093:z-Val-Ala-Asp(Ome)-fluoromethylketone; D004317:Doxorubicin; D003513:Cycloheximide; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1