Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II.
Ruben G G LeendersShoshy Alam BrinchSven T SowaEnya Amundsen-IsaksenAlbert Galera-PratSudarshan MurthySjoerd AertssenJohannes N SmitsPiotr NieczyporEddy DamenAnita WegertMarc NazareLari LehtiöShoshy A BrinchStefan KraussPublished in: Journal of medicinal chemistry (2021)
Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure-activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC50 inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.
Keyphrases
- small molecule
- cell proliferation
- structure activity relationship
- stem cells
- endothelial cells
- randomized controlled trial
- epithelial mesenchymal transition
- high glucose
- papillary thyroid
- social media
- crispr cas
- metabolic syndrome
- type diabetes
- molecular docking
- high throughput
- squamous cell
- risk assessment
- cancer therapy
- skeletal muscle
- squamous cell carcinoma
- oxidative stress
- pi k akt
- protein protein
- endoplasmic reticulum stress
- glycemic control
- insulin resistance
- replacement therapy