FIKK Kinase, a Ser/Thr Kinase Important to Malaria Parasites, Is Inhibited by Tyrosine Kinase Inhibitors

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2018 Jul 20

PMID 30023525

Citations 7

Authors

Benjamin C Lin

Darcy R Harris

Lucy M D Kirkman

Astrid M Perez

Yiwen Qian

Janse T Schermerhorn

Min Y Hong

Dennis S Winston

Lingyin Xu

Gabriel S Brandt

Affiliations

Soon will be listed here.

Abstract

A relatively high-affinity inhibitor of FIKK kinase from the malaria parasite was identified by in vitro assay of recombinant kinase. The FIKK kinase family is unique to parasitic organisms of the Apicomplexan order and has been shown to be critical in malaria parasites. The recombinant kinase domain was expressed and screened against a small molecule library, revealing a number of tyrosine kinase inhibitors that block FIKK kinase activity. A family of tyrphostins was further investigated, to begin exploring the FIKK kinase pharmacophore. Finally, emodin was identified as a relatively high-affinity FIKK kinase inhibitor, identifying this family of anthraquinones as potential lead compounds for the development of antimalarials targeting the FIKK kinase.

Citing Articles

Qualitative and quantitative analysis methods for quality control of rhubarb in Taiwan's markets.

Au T, Ho Y, Chang Y Front Pharmacol. 2024; 15:1364460.

PMID: 38746013 PMC: 11091417. DOI: 10.3389/fphar.2024.1364460.

Plasmodium falciparum FIKK 9.1 kinase modeling to screen and identify potent antimalarial agents from chemical library.

Kumar D, Karjee P, Prasad M, Punniyamurthy T, Trivedi V 3 Biotech. 2023; 13(8):277.

PMID: 37476548 PMC: 10354315. DOI: 10.1007/s13205-023-03677-x.

Botanical Medicines Cryptolepis sanguinolenta, Artemisia annua, Scutellaria baicalensis, Polygonum cuspidatum, and Alchornea cordifolia Demonstrate Inhibitory Activity Against Babesia duncani.

Zhang Y, Alvarez-Manzo H, Leone J, Schweig S, Zhang Y Front Cell Infect Microbiol. 2021; 11:624745.

PMID: 33763384 PMC: 7982592. DOI: 10.3389/fcimb.2021.624745.

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments.

Mustiere R, Vanelle P, Primas N Molecules. 2020; 25(24).

PMID: 33334080 PMC: 7765515. DOI: 10.3390/molecules25245949.

Compounds from Natural Sources as Protein Kinase Inhibitors.

Baier A, Szyszka R Biomolecules. 2020; 10(11).

PMID: 33198400 PMC: 7698043. DOI: 10.3390/biom10111546.

References

Levitzki A, Mishani E . Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem. 2006; 75:93-109. DOI: 10.1146/annurev.biochem.75.103004.142657. View

Peranen J, Rikkonen M, Hyvonen M, Kaariainen L . T7 vectors with modified T7lac promoter for expression of proteins in Escherichia coli. Anal Biochem. 1996; 236(2):371-3. DOI: 10.1006/abio.1996.0187. View

Ronald P, Beutler B . Plant and animal sensors of conserved microbial signatures. Science. 2010; 330(6007):1061-4. DOI: 10.1126/science.1189468. View

Wang Q, Zorn J, Kuriyan J . A structural atlas of kinases inhibited by clinically approved drugs. Methods Enzymol. 2014; 548:23-67. DOI: 10.1016/B978-0-12-397918-6.00002-1. View

Ward P, Equinet L, Packer J, Doerig C . Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics. 2004; 5:79. PMC: 526369. DOI: 10.1186/1471-2164-5-79. View

Osman K, Ye J, Shi Z, Toker C, Lovato D, Jumani R . Discovery and structure activity relationship of the first potent cryptosporidium FIKK kinase inhibitor. Bioorg Med Chem. 2017; 25(5):1672-1680. DOI: 10.1016/j.bmc.2017.01.036. View

Endicott J, Noble M, Johnson L . The structural basis for control of eukaryotic protein kinases. Annu Rev Biochem. 2012; 81:587-613. DOI: 10.1146/annurev-biochem-052410-090317. View

Taylor S, Shaw A, Hu J, Meharena H, Kornev A . Pseudokinases from a structural perspective. Biochem Soc Trans. 2013; 41(4):981-6. PMC: 4399968. DOI: 10.1042/BST20130120. View

Nunes M, Goldring J, Doerig C, Scherf A . A novel protein kinase family in Plasmodium falciparum is differentially transcribed and secreted to various cellular compartments of the host cell. Mol Microbiol. 2006; 63(2):391-403. DOI: 10.1111/j.1365-2958.2006.05521.x. View

10.

Schneider A, Mercereau-Puijalon O . A new Apicomplexa-specific protein kinase family: multiple members in Plasmodium falciparum, all with an export signature. BMC Genomics. 2005; 6:30. PMC: 1079819. DOI: 10.1186/1471-2164-6-30. View

11.

Dar A, Shokat K . The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem. 2011; 80:769-95. DOI: 10.1146/annurev-biochem-090308-173656. View

12.

Jaijyan D, Verma P, Prasad Singh A . A novel FIKK kinase regulates the development of mosquito and liver stages of the malaria. Sci Rep. 2016; 6:39285. PMC: 5172157. DOI: 10.1038/srep39285. View

13.

Skariah S, Walwyn O, Engelberg K, Gubbels M, Gaylets C, Kim N . The FIKK kinase of Toxoplasma gondii is not essential for the parasite's lytic cycle. Int J Parasitol. 2016; 46(5-6):323-32. PMC: 4844859. DOI: 10.1016/j.ijpara.2016.01.001. View

14.

Doerig C, Abdi A, Bland N, Eschenlauer S, Dorin-Semblat D, Fennell C . Malaria: targeting parasite and host cell kinomes. Biochim Biophys Acta. 2009; 1804(3):604-12. DOI: 10.1016/j.bbapap.2009.10.009. View

15.

Aurrecoechea C, Heiges M, Wang H, Wang Z, Fischer S, Rhodes P . ApiDB: integrated resources for the apicomplexan bioinformatics resource center. Nucleic Acids Res. 2006; 35(Database issue):D427-30. PMC: 1669770. DOI: 10.1093/nar/gkl880. View

16.

Yuan J, Johnson R, Huang R, Wichterman J, Jiang H, Hayton K . Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum. Nat Chem Biol. 2009; 5(10):765-71. PMC: 2784992. DOI: 10.1038/nchembio.215. View

17.

Cowman A, Healer J, Marapana D, Marsh K . Malaria: Biology and Disease. Cell. 2016; 167(3):610-624. DOI: 10.1016/j.cell.2016.07.055. View

18.

Hsu H, Liu L, Wang H, Hung C, Lin Y, Ho C . Stromal Fibroblasts from the Interface Zone of Triple Negative Breast Carcinomas Induced Epithelial-Mesenchymal Transition and its Inhibition by Emodin. PLoS One. 2017; 12(1):e0164661. PMC: 5218416. DOI: 10.1371/journal.pone.0164661. View

19.

Jiang Z, McKnight C . A phosphorylation-induced conformation change in dematin headpiece. Structure. 2006; 14(2):379-87. DOI: 10.1016/j.str.2005.11.007. View

20.

Knight Z, Shokat K . Features of selective kinase inhibitors. Chem Biol. 2005; 12(6):621-37. DOI: 10.1016/j.chembiol.2005.04.011. View