2. Academic Validation
  3. Human Polo-like Kinase Inhibitors as Antiplasmodials

Human Polo-like Kinase Inhibitors as Antiplasmodials

  • ACS Infect Dis. 2023 Mar 15. doi: 10.1021/acsinfecdis.3c00025.
Monica J Bohmer 1,  Jinhua Wang 2 3,  Eva S Istvan 4,  Madeline R Luth 5,  Jennifer E Collins 1,  Edward L Huttlin 6,  Lushun Wang 7,  Nimisha Mittal 5,  Mingfeng Hao 2 3,  Nicholas P Kwiatkowski 2 3,  Steven P Gygi 6,  Ratna Chakrabarti 8,  Xianming Deng 9,  Daniel E Goldberg 4,  Elizabeth A Winzeler 5,  Nathanael S Gray 7,  Debopam Chakrabarti 1
Affiliations

Affiliations

  • 1 Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3 Department of Cancer Biolo gy, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Division of Infectious Diseases, Department of Medicine and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 5 Department of Pediatrics, School of Medicine, University California, San Diego, La Jolla, California 92093, United States.
  • 6 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 7 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 8 Division of Cancer Research, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida 32826, United States.
  • 9 School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
PMID: 36919909 DOI: 10.1021/acsinfecdis.3c00025
Abstract

Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment of Cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium. A subset of these inhibitors was profiled for their in vitro killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an Aminoacyl-tRNA Synthetase.

Keywords

NEK; PLK; Plasmodium; antimalarial; antiplasmodial; kinase; malaria.

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