Lysine targeting covalent inhibitors of malarial kinase <i>Pf</i>CLK3.

ABSTRACT: Malaria continues to devastate tropical regions of the world, with resistance to frontline drugs on the rise. Kinase inhibition has emerged as a promising novel mechanism of action in the fight against malaria. We previously reported the development of TCMDC-135051 (1), a highly potent, multi-stage inhibitor of Plasmodium falciparum CLK3 (PfCLK3). Building on this work, we subsequently developed the first covalent kinase inhibitor for malaria, selectively targeting a unique cysteine residue. Despite their high potency and selectivity, covalent inhibitors that target cysteine residues are particularly vulnerable to resistance arising from single point mutations of the nucleophilic residue. This work presents a novel strategy targeting the essential kinase catalytic lysine resi

SUBMITTER: Brettell SB 

PROVIDER: S-EPMC12164071 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature