Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein.
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.
Department of Physics, Federal University of São Carlos, São Carlos, Brazil.
Stella
S
Hernandez Maganhi
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Patrizia
P
Jensen
Department of Physics, Federal University of São Carlos, São Carlos, Brazil.
Ignez
I
Caracelli
Department of Chemistry, Federal University of São Carlos, São Carlos, Brazil.
Julio
J
Zukerman Schpector
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
Stefan
S
Fröhling
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.|Centre of Excellence "Biomaterials Chemistry", Linnaeus University, 391 82 Kalmar, Sweden.
Ran
0000-0001-8696-3104
R
Friedman
D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology
D009363:Neoplasm Proteins; D010879:Piperazines; D011725:Pyridines; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib
DFG motif; molecular dynamics; protein-drug interactions; resistance mutations