P albociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein
Open accessAbstract
Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary-based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein-drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well-conserved DFG motif of the kinase. Interestingly, CDK6-dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein-drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.
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In the CDK4 allosteric site, the scaffold could interact with surrounding hydrophobic residues and residues in the DFG-loop, avoiding interactions with the highly conserved ATP-binding site that might reduce selectivity for CDK4.
“In the CDK4 allosteric site, the scaffold could interact with surrounding hydrophobic residues and residues in the DFG-loop, avoiding interactions with the highly conserved ATP-binding site that might reduce selectivity for CDK487.”
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Wang, B., Peng, F., Huang, W., Zhou, J., Zhang, N., Sheng, J., Haruehanroengra, P., He, G., & Han, B. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.12.013 · Cited by 73 · see citing works
- Authors
- Hernandez Maganhi, S., Jensen, P., Caracelli, I., Zukerman Schpector, J., Fröhling, S., & Friedman, R.
- Affiliations
- Department of Physics Federal University of São Carlos São Carlos Brazil
- German Cancer Research Center (DE)
- Universidade Federal de São Carlos (BR)
- Department of Chemistry Federal University of São Carlos São Carlos Brazil
- Linnaeus University (SE)
- Corresponding author
- Friedman, Ran
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2017-03-06
- Volume
- 26
- Issue
- 4
- Pages
- 870-879
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC5368058
- OpenAlex
- W2587761530
- Cited by
- 25
- References
- 44
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 3
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Protein Science (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Swedish Research Council (2014–4406)
- Swedish Cancer Society (CAN 2015/387)
- German Research Foundation (FR 2113/4‐1)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (306121/2013‐2, 305626/2013‐2)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2014/05227‐6)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- palbociclib, CDK6, cyclin-dependent kinase 4/6 inhibitors, drug resistance, drug-protein interactions, hydrogen bonding, hydrophobic interactions, DFG motif, acute myeloid leukemia, breast cancer, molecular dynamics simulation, kinase activity
- MeSH terms
- Humans, Hydrogen Bonding, Neoplasm Proteins, Piperazines, Pyridines, Leukemia, Myeloid, Acute, Amino Acid Substitution, Mutation, Missense, Amino Acid Motifs, Cell Line, Tumor, Cyclin-Dependent Kinase 6, Molecular Dynamics Simulation
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