基于喹唑啉的强效、选择性和口服生物可用性 STK17A/B 双抑制剂

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-20 DOI:10.1021/acsmedchemlett.4c00125

Sana Chaudhry, Jesus R. Castro, Tulasigeri M. Totiger, Jumana Afaghani, Rabia Khurshid, Miah Nicholls, Ziming Zhang, Stephan C. Schürer, Ashish Shah, Justin Taylor* and Yangbo Feng*,

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引用次数: 0

摘要

STK17A 是丝氨酸和苏氨酸激酶死亡相关蛋白家族中一个尚未定性的新成员。在许多癌症中都能观察到 STK17A 的过表达。我们发现了一种基于喹唑啉核心的先导化合物。对先导化合物进行优化后，我们发现了具有类似药物性质和口服生物利用度的强效选择性 STK17A/B 抑制剂。化合物 9 的 STK17A 抑制作用 IC50 为 23 nM。根据针对两个野生型激酶面板（分别为 375 和 398 个激酶）的分析研究，化合物 9 对 STK17A 和 STK17B 都有很强的抑制作用，但只对 AAK1、MYLK4 和 NEK3/5 有中度的脱靶抑制作用。此外，化合物 9 具有良好的口服生物利用度，为针对各种癌症的体内研究铺平了道路。

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Potent, Selective, and Orally Bioavailable Quinazoline-Based STK17A/B Dual Inhibitors

STK17A is a novel uncharacterized member of the death-associated protein family of serine and threonine kinases. Overexpression of STK17A is observed in many cancers. We identified a lead compound that is based on a quinazoline core. Optimizations of the lead compound led to the discovery of potent and selective STK17A/B inhibitors with drug-like properties and oral bioavailability. Compound 9 had an STK17A inhibitory IC₅₀ of 23 nM. Based on profiling studies against two wild-type kinase panels (375 and 398 kinases, respectively), compound 9 had strong inhibition of both STK17A and STK17B but moderate off-target inhibition only for AAK1, MYLK4, and NEK3/5. In addition, compound 9 had good oral bioavailability, paving the way for in vivo studies against various cancers.

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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.