ArticleCell cycle (Georgetown, Tex.)2014
Structure-based discovery of the first allosteric inhibitors of cyclin-dependent kinase 2.
Article in Cell cycle (Georgetown, Tex.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 52 citations in OpenAlex.
- Fine-Tuning DiffDock-L for Allosteric Kinase Docking.Journal of chemical information and modeling · 2026Article
- Can Deep Learning Blind Docking Methods be Used to Predict Allosteric Compounds?Journal of chemical information and modeling · 2025Article
- Targeting cyclin-dependent kinase 2 (CDK2) interactions with cyclins and Speedy 1 (Spy1) for cancer and male contraception.Future medicinal chemistry · 2025Review
- CDK2 Allosteric Modulators: The New Route in the Design of New Drugs as Anticancer and Non-hormonal Contraceptives.Current medicinal chemistry · 2025Review
- Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice.Journal of medicinal chemistry · 2023Article
- On the development of B-Raf inhibitors acting through innovative mechanisms.F1000Research · 2022Article
- Utilization of kinase inhibitors as novel therapeutic drug targets: A review.Oncology research · 2022Review
- Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†.Biology of reproduction · 2020Review
- Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma.Acta pharmaceutica Sinica. B · 2020Article
- Cooperativity Between Orthosteric Inhibitors and Allosteric Inhibitor 8-Anilino-1-Naphthalene Sulfonic Acid (ANS) in Cyclin-Dependent Kinase 2.ACS chemical biology · 2020Article
- In Silico Repositioning of Cannabigerol as a Novel Inhibitor of the Enoyl Acyl Carrier Protein (ACP) Reductase (InhA).Molecules (Basel, Switzerland) · 2019Article
- Refinement and Rescoring of Virtual Screening Results.Frontiers in chemistry · 2019Article
- Article
- Review
- High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery.Angewandte Chemie (International ed. in English) · 2018Article
- Predicting Protein Dynamics and Allostery Using Multi-Protein Atomic Distance Constraints.Structure (London, England : 1993) · 2017Article
- Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine.Molecules (Basel, Switzerland) · 2016Article
- Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2.International journal of molecular sciences · 2015Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Allosteric targeting of protein kinases via displacement of the structural αC helix with type III allosteric inhibitors is currently gaining a foothold in drug discovery. Recently, the first crystal structure of CDK2 with an open allosteric pocket adjacent to the αC helix has been described, prospecting new opportunities to design more selective inhibitors, but the structure has not yet been exploited for the structure-based design of type III allosteric inhibitors. In this work we report the results of a virtual screening campaign that resulted in the discovery of the first-in-class type III allosteric ligands of CDK2. Using a combination of docking and post-docking analyses made with our tool BEAR, 7 allosteric ligands (hit rate of 20%) with micromolar affinity for CDK2 were identified, some of them inhibiting the growth of breast cancer cell lines in the micromolar range. Competition experiments performed in the presence of the ATP-competitive inhibitor staurosporine confirmed that the 7 ligands are truly allosteric, in agreement with their design. Of these, compound 2 bound CDK2 with an EC50 value of 3 μM and inhibited the proliferation of MDA-MB231 and ZR-75-1 breast cancer cells with IC50 values of approximately 20 μM, while compound 4 had an EC50 value of 71 μM and IC50 values around 4 μM. Remarkably, the most potent compound 4 was able to selectively inhibit CDK2-mediated Retinoblastoma phosphorylation, confirming that its mechanism of action is fully compatible with a selective inhibition of CDK2 phosphorylation in cells. Finally, hit expansion through analog search of the most potent inhibitor 4 revealed an additional ligand 4g with similar in vitro potency on breast cancer cells.
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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.