Repositioning a Human Kinase Platelet-Derived Growth Factor Receptor Alpha Type II Inhibitor for Malaria and Inhibition of Hemozoin Formation
A type II Platelet-Derived Growth Factor Receptor Alpha <b>(</b>PDGFRA) human kinase inhibitor <b>GSK190937</b>, with antiplasmodium activity against asexual blood stage parasites (<i>Pf</i>NF54 IC<sub>50</sub> = 0.22 μM) was identified from the Kinase Chemogenomics Set, a collection of narrow-spectrum human kinase inhibitors. Medicinal chemistry progression of the hit focused on improving potency, selectivity, and ADME properties, leading to compounds <b>20</b>, <b>23</b>, and <b>29</b> with improved microsomal metabolic stability and asexual blood stage antiplasmodium activity. Mechanism of action studies showed that this series inhibits hemozoin formation, killing late-stage trophozoites.
Authors
- Mathew Njoroge (ORCID: https://orcid.org/0000-0003-1276-2224)
- David Taylor (ORCID: https://orcid.org/0000-0001-9762-7878)
- Godwin Akpeko Dziwornu (ORCID: https://orcid.org/0000-0003-1668-8818)
- Lauren B. Coulson (ORCID: https://orcid.org/0000-0003-4699-0428)
- Kathryn J. Wicht (ORCID: https://orcid.org/0000-0001-6145-9956)
- Keletso Maepa
- Mmakwena M. Mmonwa
- James C. Burrows
- Oluwatosin Y Audu
- Keabetswe Masike
- Liso Tshaka
- Kelly Chibale
- Preshen Govender
Institutions
- South African Medical Research Council (ZA)
- University of Zululand (ZA)
- University of Cape Town (ZA)
- Discovery Centre (CA)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-12-26
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00560
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00