Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore

Han Wee Ong; Anna Truong; Frank Kwarcinski; Chandi de Silva; Krisha Avalani; Tammy M Havener; Michael Chirgwin; Kareem A Galal; Caleb Willis; Andreas Krämer; Shubin Liu; Stefan Knapp; Emily R Derbyshire; Reena Zutshi; David H Drewry

doi:10.1016/j.ejmech.2022.115043

Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore

Eur J Med Chem. 2023 Mar 5:249:115043. doi: 10.1016/j.ejmech.2022.115043. Epub 2022 Dec 30.

Authors

Affiliations

¹ Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
² Department of Chemistry, Duke University, 124 Science Drive, Durham, NC, 27708, USA.
³ Luceome Biotechnologies, L.L.C, 1665 E. 18th Street, Suite 106, Tucson, AZ, 85719, USA.
⁴ Structural Genomics Consortium, Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
⁵ Research Computing Center, University of North Carolina, Chapel Hill, NC, 27599-3420, USA; Department of Chemistry, University of North Carolina, Chapel Hill, NC, 27599-3420, USA.
⁶ Department of Chemistry, Duke University, 124 Science Drive, Durham, NC, 27708, USA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, 213 Research Drive, Durham, NC, 27710, USA. Electronic address: [email protected].
⁷ Luceome Biotechnologies, L.L.C, 1665 E. 18th Street, Suite 106, Tucson, AZ, 85719, USA. Electronic address: [email protected].
⁸ Structural Genomics Consortium and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].

Abstract

Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivatives were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compound 67, a PfPK6 inhibitor (IC₅₀ = 13 nM) active against the P. falciparum blood stage (EC₅₀ = 160 nM), and compound 79, a PfPK6 inhibitor (IC₅₀ < 5 nM) with dual-stage antiplasmodial activity against P. falciparum blood stage (EC₅₀ = 39 nM) and against P. berghei liver stage (EC₅₀ = 220 nM).

Keywords: Antiplasmodial; Group efficiency; Kinase inhibitor; Malaria; Plasmodium falciparum Protein kinase 6 (PfPK6); Structure-activity relationship study.

MeSH terms

Antimalarials* / pharmacology
Antimalarials* / therapeutic use
Humans
Malaria, Falciparum* / drug therapy
Pharmacophore
Plasmodium berghei
Plasmodium falciparum
Protein Kinases

Substances

Antimalarials
Protein Kinases

Grants and funding

R44 AI150237/AI/NIAID NIH HHS/United States