ArticleJournal of medicinal chemistry2015
Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed.
- Mediator Kinase Inhibitor Selectivity and Activity in Colorectal Cancer.ACS chemical biology · 2025Article
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.Signal transduction and targeted therapy · 2025Review
- Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming.Research square · 2024Article
- Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.NPJ precision oncology · 2024Article
- Targeting super-enhancer activity for colorectal cancer therapy.American journal of translational research · 2024Review
- Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers.Research square · 2023Article
- Targeting transcription cycles in cancer.Nature reviews. Cancer · 2022Review
- Development of Highly Potent and Selective Pyrazolopyridine Inhibitor of CDK8/19.ACS medicinal chemistry letters · 2021Article
- Identification and characterization of the mediator kinase-dependent myometrial stem cell phosphoproteome.F&S science · 2021Article
- Systemic Toxicity Reported for CDK8/19 Inhibitors CCT251921 and MSC2530818 Is Not Due to Target Inhibition.Cells · 2019Article
- Therapeutic targeting of transcriptional cyclin-dependent kinases.Transcription · 2019Review
- Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review).International journal of molecular medicine · 2018Review
- Treatment with XAV-939 prevents in vitro calcification of human valvular interstitial cells.PloS one · 2018Article
- Novel molecular insights and new therapeutic strategies in osteosarcoma.Cancer cell international · 2018Review
- CDK8 Kinase Activity Promotes Glycolysis.Cell reports · 2017Article
- WNT signalling in prostate cancer.Nature reviews. Urology · 2017Review
- SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains.Oncotarget · 2017Article
- Inhibitors of cyclin-dependent kinases as cancer therapeutics.Pharmacology & therapeutics · 2017Review
- Article
Corrections and comments
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Authors and funding
32 authors.
Funding
Abstract
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.