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  • 1.
    Bjelic, Sinisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Protein carriers for passage of the Blood-Brain Barrier2015In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, p. 177-177Article in journal (Other academic)
  • 2.
    Maganhi, Stella Hernandez
    et al.
    Federal University of São Carlos, Brazil.
    Jensen, Patrizia
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany.
    Caracelli, Ignez
    Federal University of São Carlos, Brazil.
    Schpector, Julio Zukerman
    Federal University of São Carlos, Brazil.
    Froehling, Stefan
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany ; Heidelberg University Hospital, Germany ; German Cancer Consortium (DKTK), Germany.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein2017In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 26, no 4, p. 870-879Article in journal (Refereed)
    Abstract [en]

    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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