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Screening for Caspase-3 Inhibitors: A New Class of Potent Small-Molecule Inhibitors of Caspase-3

ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121; Chemical Diversity Research Institute, Khimki, Moscow Region, Russia 114401 io{at}chemdiv.com

Sergei Malarchuk

Elena Dubrovskaya

Alexander Khvat

Sergey Tkachenko

Volodymyr Kysil

ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121

Alexey Ilyin

Dmitry Kravchenko

Chemical Diversity Research Institute, Khimki, Moscow Region, Russia 114401

Eric R. Prossnitz

Larry Sklar

University of New Mexico, 915 Camino de Salud NE, Albuquerque, NM

Alexandre Ivachtchenko

ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121; Chemical Diversity Research Institute, Khimki, Moscow Region, Russia 114401

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 electrophilicwarhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and antiapoptosis 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 staurosporineinduced apoptosis in a few cell lines and retinoic acid–induced apoptosis in zebrafish.

Key Words: caspase-3 • small molecules • inhibitors • apoptosis • structure-activity relationship

This version was published on April 1, 2006

Journal of Biomolecular Screening, Vol. 11, No. 3, 277-285 (2006)
DOI: 10.1177/1087057105285048


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