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

Abstract

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.

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

“…Preliminary docking studies and integrative molecular simulations suggested that an inhibitor bearing a planar THN would bind well to CDK4 and MDM2. 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 87 . At the P53-binding site in MDM2, the THN-fused C3-spirooxindole could form hydrogen bonds and hydrophobic interactions mimicking Phe19, Trp23 and Leu25 of P53.…”

Computer simulations of the signalling network in FLT3 +-acute myeloid leukaemia – indications for an optimal dosage of inhibitors against FLT3 and CDK6

“…The CDK6 inhibitors palbociclib and ribociclib are used in the treatment of advanced-stage oestrogen receptor (ER)-positive breast cancer [ 68 ] and may be used in other cancers as well (including AML [ 69 ]). Resistance mutations to palbociclib have hitherto not been detected, perhaps due to its binding mode [ 70 ]. Thus, both CDK6 and HCK may be relevant drug targets in FLT3 + -AML in addition to FLT3.…”

Clinical significance of detecting CSF-derived tumor cells in breast cancer patients with leptomeningeal metastasis

“…Based on these previous studies and our sequencing data, we chose to use PARP inhibitor Olaparib, PI3K inhibitor BKM120, tyrosine kinase inhibitor lapatinib. Several studies reported that Palbociclib could overcome CDK6 mutations (D163G, H100L) [ 14 , 15 ]. We proposed CDK4/6 inhibitor palbociclib that would target CDK6 gene mutation (V77G) carried by CSFTCs in this case.…”