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

¹ ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121.; Chemical Diversity Research Institute, Khimki, Moscow Region, Russia 114401.
² ChemDiv, Inc., 11885 Sorrento Valley Road, San Diego, CA 92121.
³ Chemical Diversity Research Institute, Khimki, Moscow Region, Russia 114401.
⁴ University of New Mexico, 915 Camino de Salud NE, Albuquerque, NM.

^* To whom correspondence should be addressed. E-mail: io{at}chemdiv.com.

	Abstract

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 antiapoptosis assays. Mechanistic analysis of a representative compound of this class, CD-001-0011, showed that the compound exhibited a high potency (IC₅₀ = 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.

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

First published on February 20, 2006, doi:10.1177/1087057105285048

Journal of Biomolecular Screening 2006;11:277.

A more recent version of this article appeared on April 1, 2006


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