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靶向 CLK3 的共价抑制剂：疟疾治疗的新策略。

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

机构信息

School of Chemistry, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.

Centre for Translational Pharmacology, The Advanced Research Centre, University of Glasgow, 11 Chapel Lane, Glasgow G11 6EW, U.K.

出版信息

J Med Chem. 2024 Nov 14;67(21):18895-18910. doi: 10.1021/acs.jmedchem.4c01300. Epub 2024 Oct 23.

DOI:10.1021/acs.jmedchem.4c01300
PMID:39441986
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11571108/
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.

摘要

疟疾每年仍导致超过 60 万人死亡，由于一线药物的耐药性不断增加，每年的死亡人数都在增加。因此，迫切需要具有新颖作用机制的新药。在这项工作中，我们解决了关键疟原虫激酶 CLK3 与可逆抑制剂 TCMDC-135051()的共晶结构，从而能够设计针对独特半胱氨酸残基（Cys368）的共价抑制剂，该残基在人类激酶组中保守性差。氯乙酰胺在重组蛋白和测定中均表现出纳摩尔效力和共价抑制作用。在 6 小时冲洗后，寄生虫中的疗效仍然存在，表明作用持续时间延长。此外，与 HepG2 细胞相比，显示出改善的激酶选择性和高选择性指数，耐药性倾向低（log MIR > 8.1）。据我们所知，化合物是第一个疟原虫激酶的共价抑制剂，为单剂量疟疾治愈提供了有希望的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/6bb049d7dc13/jm4c01300_0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/9058c100e2c8/jm4c01300_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/af5c8294d7f4/jm4c01300_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/bdb46ff81ab3/jm4c01300_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/b0077851da4f/jm4c01300_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/82a24b1b86df/jm4c01300_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/96ba5a16fdbf/jm4c01300_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/40cc6300fef9/jm4c01300_0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a04/11571108/6bb049d7dc13/jm4c01300_0009.jpg

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