Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.
Administration, Oral
Animals
Cell Line, Tumor
Colonic Neoplasms
/ drug therapy
Drug Design
Drug Discovery
/ methods
Enzyme Inhibitors
/ administration & dosage
Female
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Protein Structure, Tertiary
Rats
Tankyrases
/ antagonists & inhibitors
Treatment Outcome
Xenograft Model Antitumor Assays
/ methods
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
23 04 2020
23 04 2020
Historique:
pubmed:
24
3
2020
medline:
25
9
2020
entrez:
24
3
2020
Statut:
ppublish
Résumé
Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.
Identifiants
pubmed: 32202790
doi: 10.1021/acs.jmedchem.0c00045
doi:
Substances chimiques
Enzyme Inhibitors
0
TNKS2 protein, human
EC 2.4.2.30
Tankyrases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM