Abstract
Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold′s phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. TNKS for the inhibitors: A tankyrase inhibitor scaffold was identified, and a set of analogues were assayed for tankyrase inhibition. As a result, several highly potent and isoenzyme-selective inhibitors were discovered. Crystal structures of the compounds in complex with tankyrase 2 allowed us to rationalize inhibitor design using this and other similar scaffolds.
Original language | English (US) |
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Pages (from-to) | 1978-1985 |
Number of pages | 8 |
Journal | ChemMedChem |
Volume | 8 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2013 |
Externally published | Yes |
Keywords
- Wnt signaling
- inhibitors
- structural biology
- structure-activity relationships
- tankyrase
ASJC Scopus subject areas
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Molecular Medicine
- Biochemistry
- Pharmacology
- Organic Chemistry