Discovery of Potent Orally Active Plasmodium N -Myristoyltransferase Inhibitors Using Fragment-Linking Approaches
Abstract N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive potential drug target for parasitic infections such as malaria and leishmaniasis. Co-crystallisation of a high-throughput screening hit with P. vivax NMT identified a novel binding mode, and cooperative binding experiments with fragments identified synergistic improvements in potency and opportunities for fragment-linking. Optimisation of the torsional angle of fragment linkage through phenolic ether enabled the desired activity spectrum and selectivity profile, and examples were progressed to a mouse malaria model, resulting in the selection of IMP-1002 for further evaluation. This early lead compound was efficacious after oral administration in a SCID mouse model and is highly active against both blood- and liver-stage forms of the parasite. Finally, we discovered that highly potent human NMT inhibitors, including IMP-1088, could be generated by introducing an additional fluorine atom to further tune the torsion angle.
Authors
- Edward W. Tate (ORCID: https://orcid.org/0000-0003-2213-5814)
- Brice Campo (ORCID: https://orcid.org/0000-0002-6425-5577)
- Richard J. Wall (ORCID: https://orcid.org/0000-0003-3487-3187)
- Robin J. Leatherbarrow (ORCID: https://orcid.org/0000-0001-8193-5964)
- Jennie A. Hutton
- Munira Grainger
- Rita Tewari (ORCID: https://orcid.org/0000-0003-3943-1847)
- Stephan Meister (ORCID: https://orcid.org/0000-0003-2436-7037)
- J.A. Brannigan (ORCID: https://orcid.org/0000-0001-6597-8972)
- Roger V. Bonnert (ORCID: https://orcid.org/0000-0002-2976-7374)
- Andrew Reid Bell (ORCID: https://orcid.org/0000-0002-1164-312X)
- Nicole B. Trainor (ORCID: https://orcid.org/0000-0002-3758-9969)
- Anthony A. Holder (ORCID: https://orcid.org/0000-0002-8490-6058)
- Anthony J. Wilkinson (ORCID: https://orcid.org/0000-0003-4577-9479)
- Elizabeth A. Winzeler (ORCID: https://orcid.org/0000-0002-4049-2113)
- Jeremy Nicholas Burrows (ORCID: https://orcid.org/0000-0001-8448-6068)
- Abhijit Kundu
Institutions
- University of Nottingham (GB)
- Liverpool School of Tropical Medicine (GB)
- The Francis Crick Institute (GB)
- University of California San Diego (US)
- TCG Lifesciences (India) (IN)
- Imperial College London (GB)
- University of York (GB)
- Medicines for Malaria Venture (CH)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00914
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00