ArticleBritish journal of pharmacology2018
Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents.
Article in British journal of pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- CDK4-selective inhibitor AU2-94 for the treatment of advanced and therapy-resistant prostate cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- A novel CDK4 inhibitor for myeloid protection in chemotherapy-treated triple-negative breast Cancer.Investigational new drugs · 2025Article
- Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.Current medicinal chemistry · 2025Review
- Article
- Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6.Journal of cancer research and clinical oncology · 2024Article
- Recent Progress in CDK4/6 Inhibitors and PROTACs.Molecules (Basel, Switzerland) · 2023Review
- Discovery ofMolecules (Basel, Switzerland) · 2023Article
- Functional Genomic Analysis of CDK4 and CDK6 Gene Dependency across Human Cancer Cell Lines.Cancer research · 2022Article
- An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9/FLT3 for the Treatment of Acute Myeloid Leukemia.Cancers · 2022Article
- Liquid Biopsy: A New Tool for Overcoming CDKi Resistance Mechanisms in Luminal Metastatic Breast Cancer.Journal of personalized medicine · 2021Review
- Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3DMolecules (Basel, Switzerland) · 2021Article
- Development of CDK4/6 Inhibitors: A Five Years Update.Molecules (Basel, Switzerland) · 2021Review
- Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs.Acta pharmaceutica Sinica. B · 2021Review
- Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer.Frontiers in pharmacology · 2020Review
- Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents.British journal of pharmacology · 2018Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeCyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6. EXPERIMENTAL APPROACH: The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling. KEY
resultsWe discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate. CONCLUSIONS AND IMPLICATIONS: We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy.
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