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Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
- Source :
- Journal of Medicinal Chemistry. 56:10003-10015
- Publication Year :
- 2013
- Publisher :
- American Chemical Society (ACS), 2013.
-
Abstract
- Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
- Subjects :
- Models, Molecular
Tankyrases
Dose-Response Relationship, Drug
Molecular Structure
biology
Chemistry
Drug discovery
Poly ADP ribose polymerase
Wnt signaling pathway
Administration, Oral
Biological Availability
Structure-Activity Relationship
Biochemistry
Drug Discovery
biology.protein
Humans
Molecular Medicine
Structure–activity relationship
Enzyme Inhibitors
Pharmacophore
Axin Protein
Polymerase
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....eba595497eee0272affa9da310eb1804