Targeting PfCLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment
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 mala...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-11, Vol.67 (21), p.18895-18910 |
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| creator | Brettell, Skye B. Janha, Omar Begen, Abbey Cann, Gillian Sharma, Saumya Olaniyan, Niniola Yelland, Tamas Hole, Alison J. Alam, Benazir Mayville, Emily Gillespie, Ross Capper, Michael Fidock, David A. Milligan, Graeme Clarke, David J. Tobin, Andrew B. Jamieson, Andrew G. |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.4c01300 |
| format | Article |
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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). 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| title | Targeting PfCLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment |
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