8RPC

Crystal structure of PfCLK3 with TCMDC-135051

This is a non-PDB format compatible entry.

Summary for 8RPC

• Entry DOI: 10.2210/pdb8rpc/pdb
• Descriptor: non-specific serine/threonine protein kinase, 4-[2-[5-(diethylaminomethyl)-2-methoxy-phenyl]-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]-2-propan-2-yl-benzoic acid, GLYCEROL, ... (6 entities in total)
• Functional Keywords: pfclk3 kinase domain, signaling protein
• Biological source: Plasmodium falciparum (malaria parasite P. falciparum)
• Total number of polymer chains: 1
• Total formula weight: 45559.48

Authors

Yelland, T.S.,Benazir, A.,Hole, A. (deposition date: 2024-01-15, release date: 2024-11-06, Last modification date: 2024-11-27)

Primary citation

Brettell, S.B.,Janha, O.,Begen, A.,Cann, G.,Sharma, S.,Olaniyan, N.,Yelland, T.,Hole, A.J.,Alam, B.,Mayville, E.,Gillespie, R.,Capper, M.,Fidock, D.A.,Milligan, G.,Clarke, D.J.,Tobin, A.B.,Jamieson, A.G.
Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment.
J.Med.Chem., 67:18895-18910, 2024

PubMed Abstract: 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.

PubMed: 39441986
DOI: 10.1021/acs.jmedchem.4c01300

Experimental method

X-RAY DIFFRACTION (2.079 Å)