开发吡啶并[2,3-d]嘧啶-7(8H)-酮支架，研制强效选择性 NUAK1 抑制剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 DOI:10.1021/acsmedchemlett.4c0057910.1021/acsmedchemlett.4c00579

Timothy P. C. Rooney, Gregory G. Aldred, David Winpenny, Helen Scott, Henriette M. G. Willems, Iryna Voytyuk, Jonathan H. Clarke, Helen K. Boffey*, Stephen P. Andrews and John Skidmore*,

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Development of the Pyrido[2,3-d]pyrimidin-7(8H)-one Scaffold toward Potent and Selective NUAK1 Inhibitors

The protein kinase NUAK1 has been implicated in various biological functions including cell adhesion, migration and proliferation. Genetic reduction of NUAK1 expression has notably been shown to lower total levels of human tau in a tauopathy mouse model, identifying this kinase as a potential therapeutic target for neurodegenerative disease. In this paper, we describe improvement of the NUAK1 potency, kinase-selectivity and pharmacokinetic properties of the brain-penetrant but unselective CDK4/CDK6/NUAK1 inhibitor ON123300. Through a scaffold-optimization approach we have identified different chemotypes delivering NUAK1 inhibition with improved potency and selectivity over CDK kinases compared with ON123300. We present ADME profiling and in vivo pharmacokinetic data for these compounds.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.