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

International Journal of Molecular Sciences

AlexT. Grupenmacher¹  SaktimayeeM. Roy²  MaurícioT. Tavares³  SimoneT. Sredni⁴  Tadanori Tomita⁴  AndersW. Bailey⁴  ConnorP. Dyer⁴  Amreena Suri⁴  Hendra Gunosewoyo⁵  AlanP. Kozikowski⁶  RobertA. Horton⁷  DavidR. Piper⁷ 

[1] Department of Ophtalmology, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil;Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA;Department of Pharmacy, University of São Paulo, São Paulo, SP 05508-900, Brazil;Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA;School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Perth, WA 6102, Australia;Star Wise Therapeutics, Madison, WI 53719, USA;Thermo Fisher Scientific, Research and Development, Biosciences Division, Carlsbad, CA 92008, USA;

关键词: CFI-400945;    CFI-400437;    R1530;    centrinone;    axitinib;    KW-2449;    alisertib;    AURK;    rhabdoid tumor;    AT/RT;    medulloblastoma;    protein kinase;    brain exposure;   

DOI  :  10.3390/ijms20092112

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown