Dataset Information

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

ABSTRACT: Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

SUBMITTER: Suri A

PROVIDER: S-EPMC6540285 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Suri Amreena A Bailey Anders W AW Tavares Maurício T MT Gunosewoyo Hendra H Dyer Connor P CP Grupenmacher Alex T AT Piper David R DR Horton Robert A RA Tomita Tadanori T Kozikowski Alan P AP Roy Saktimayee M SM Sredni Simone T ST

International journal of molecular sciences 20190429 9

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centri ...[more]

PMID: 31035676

Similar Datasets

Project description:Abstract BACKGROUND: In previous work we established that PLK4 is overexpressed and essential for proliferation and survival of pediatric embryonal brain tumors. PLK4 is a cell cycle-regulated protein recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. We demonstrated that PLK4 inhibition exerts a potent cytostatic effect in EBT. We also established the synergism of the PLK4 inhibitor CFI-400945 with cytotoxic drugs and other signal transduction modulators. METHODS: We studied protein kinase inhibitors (PKI) with PLK4 cross-over potential (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, alisertib and KW-2449) by assessing their chemical profiles through docking simulations over PLK4 (PDB entry: 3COK) using Gold 5.4 software; evaluating their potential to penetrate the BBB (via logBB calculation by Clark equation), performing LanthaScreen EU Kinase Binding assays (ThermoFisher Scientific) and cell based studies (viability and proliferation) in multiple embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). RESULTS: Kinase binding assays and cell based studies showed that CFI-400437 was the most effective compound, yielding an IC50 <5nM in the binding assay and requiring <100nM of drug to significantly inhibit proliferation in multiple cell lines. However, docking simulations using the PLK4 catalytic cavity and each of the various PKIs demonstrated that all of the inhibitors tested exhibit similar interactions within the binding cavity, engaging in H-bonding with backbone residues Glu-89 and Cys-91. Additional polar and hydrophobic (?-stacking) interactions were also identified for each of the PKIs. LogBB calculations revealed that compound R-1530 has the greatest likelihood to enter the brain (LogBB+0.130). CONCLUSION: Although CFI-400945 is the most effective PLK4 inhibitor among those assayed, it has low potential for BBB exposure. Molecular docking results indicate the potential to develop new chemical entities with higher BBB exposure potential using a similar binding mode to that of CFI-400945.

Dataset Information

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Publications

Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets