Discovery of Potent Orally Active Plasmodium N -Myristoyltransferase Inhibitors Using Fragment-Linking Approaches
Andrew S. Bell, Jennie A. Hutton, James A. Brannigan, Nicole Trainor, Munira Grainger, Stephan Meister, Roger Bonnert, Jeremy N. Burrows, Brice Campo, Richard J. Wall, Abhijit Kundu, Anthony J. Wilkinson, Anthony A. Holder, Elizabeth A. Winzeler, Rita Tewari, Robin J. Leatherbarrow, Edward W. TateAbstract
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.