Screening for caspase-3 inhibitors: a new class of potent small-molecule inhibitors of caspase-3.
From the authors' 650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and anti-apoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC (50)=130 nM), was reversible though noncompetitive, and had a broad selectivity profile to other caspases belonging to groups I to III. The compound was effective in preventing staurosporine induced apoptosis in a few cell lines and retinoic acid-induced apoptosis in zebrafish.
ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121, USA. io@chemdiv.com
Ilya
I
Okun
Sergei
S
Malarchuk
Elena
E
Dubrovskaya
Alexander
A
Khvat
Sergey
S
Tkachenko
Volodymyr
V
Kysil
Alexey
A
Ilyin
Dmitry
D
Kravchenko
Eric R
ER
Prossnitz
Larry
L
Sklar
Alexandre
A
Ivachtchenko
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D015027:Zebrafish
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D011804:Quinolines; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3