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

Malaria still causes over 600,000 deaths annually, with rising resistance to frontline drugs by 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 CLK3 with the reversible inhibitor TCMDC-135051 (), enabling the design of covalent inhibitors targeting a unique cysteine residue (Cys368) poorly conserved in the human kinome. Chloroacetamide shows nanomolar potency and covalent inhibition in both recombinant protein and assays. Efficacy in parasites persisted after a 6 h washout, indicating an extended duration of action. Additionally, 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 is the first covalent inhibitor of a malarial kinase, offering promising potential as a lead for a single-dose malaria cure.