2. Academic Validation
  3. Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment

Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment

  • J Med Chem. 2024 Nov 14;67(21):18895-18910. doi: 10.1021/acs.jmedchem.4c01300.
Skye B Brettell 1,  Omar Janha 2,  Abbey Begen 3,  Gillian Cann 3,  Saumya Sharma 3,  Niniola Olaniyan 2,  Tamas Yelland 4,  Alison J Hole 4,  Benazir Alam 4,  Emily Mayville 5,  Ross Gillespie 1,  Michael Capper 1,  David A Fidock 5,  Graeme Milligan 2,  David J Clarke 6,  Andrew B Tobin 2,  Andrew G Jamieson 1
Affiliations

Affiliations

  • 1 School of Chemistry, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.
  • 2 Centre for Translational Pharmacology, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.
  • 3 KelticPharma Therapeutics, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.
  • 4 Evotec (U.K.) Ltd, 95 Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, U.K.
  • 5 Department of Microbiology& Immunology and Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Medical Centre, New York, New York 10032, United States.
  • 6 EaSTCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David, Brewster Road, Edinburgh EH9 3FJ, U.K.
PMID: 39441986 DOI: 10.1021/acs.jmedchem.4c01300
Abstract

Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by Plasmodium falciparum increasing this number each year. New medicines with novel mechanisms of action are, therefore, urgently needed. In this work, we solved the cocrystal structure of the essential malarial kinase PfCLK3 with the reversible inhibitor TCMDC-135051 (1), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide 4 shows nanomolar potency and covalent inhibition in both recombinant protein and P. falciparum assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally, 4 showed improved kinase selectivity and a high selectivity index against HepG2 cells, with a low propensity for resistance (log MIR > 8.1). To our knowledge, compound 4 is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.

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