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Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the

Stella Hernandez Maganhi1, Patrizia Jensen2, Ignez Caracelli1

  • 1Department of Physics, Federal University of São Carlos, São Carlos, Brazil.

Protein Science : a Publication of the Protein Society
|February 8, 2017
PubMed

Insights

Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, shows promise in treating certain leukemias. Molecular simulations revealed novel interactions stabilizing palbociclib binding, and predicted drug resistance mutations did not impact its efficacy in acute myeloid leukemia cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinases (CDKs) 4 and 6 are crucial regulators of the cell cycle and are significant drug targets in oncology.
  • Palbociclib, a selective CDK4/6 inhibitor, is approved for breast cancer and exhibits activity in models of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML).

Purpose of the Study:

  • To investigate the molecular interactions between palbociclib and CDK6 using molecular dynamics simulations.
  • To identify potential drug resistance mechanisms and validate their impact on palbociclib efficacy in AML models.

Main Methods:

  • Molecular dynamics simulations to analyze palbociclib-CDK6 interactions.
  • Bioinformatic analysis to predict drug-resistant mutants.
  • Functional studies using CDK6-dependent human AML cell lines expressing predicted mutants.

Main Results:

  • Simulations identified previously unreported interactions, including a hydrogen bond to His 100 and hydrophobic contacts, stabilizing palbociclib binding.
  • Predicted resistance mutations (D163G and H100L) were identified based on loss of key interactions.
  • AML cells expressing these mutants remained sensitive to palbociclib, and the DFG motif mutation (D163G) did not impair catalytic activity.

Conclusions:

  • Novel interactions stabilize palbociclib binding to CDK6.
  • Predicted resistance mutations did not confer resistance in vitro, suggesting complex resistance mechanisms in vivo.
  • Palbociclib's efficacy in AML warrants further investigation, as predicted resistance mutations did not abrogate its activity.
Keywords:
DFG motifmolecular dynamicsprotein-drug interactionsresistance mutations

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