Structure–Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-01 DOI:10.1021/acsmedchemlett.6c00199

Daniel T. Webb, Katherine L. Jones, Gerald Keil, Matthew Holt, Nicholas Richards, Yvonne Walker, Andrea Taylor, Maryam Ahmadi, Lampros Milanos, Natsuko Macabuag, Eilidh Bush, Matthew Gill, Rebecca Penrose, David M. Lindsay, William J. Kerr, William Esmieu

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引用次数: 0

Abstract

Salt-inducible kinases (SIK1/2/3) belong to the AMPK family of serine/threonine kinases, and SIK inhibition has been identified as a promising strategy for therapeutic intervention in oncology and immunology. Herein, we describe the use of parallel chemistry approaches to facilitate the development of novel SIK inhibitors. From these efforts, potent pan-SIK inhibitors were identified, as well as compounds which demonstrated biased isoform selectivity toward SIK3, and possessed attractive in vitro ADME properties. To validate the most promising compounds as high-quality chemical tools, cellular target engagement was assessed using NanoBRET assays, and selectivity was investigated across the wider kinome. Finally, the pharmacological effects of several compounds were studied using cellular models of acute myeloid leukemia, resulting in the identification of potent antiproliferative agents. The compounds reported represent high-quality chemical tools of potential value for target validation studies and could serve as effective starting points for a lead optimization campaign.

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结构-活性关系研究导致有效和选择性盐诱导激酶抑制剂的鉴定

盐诱导激酶（SIK1/2/3）属于丝氨酸/苏氨酸激酶ampk家族，抑制SIK已被确定为肿瘤和免疫学治疗干预的有希望的策略。在这里，我们描述了平行化学方法的使用，以促进新的SIK抑制剂的发展。从这些努力中，鉴定出了有效的泛sik抑制剂，以及对SIK3表现出偏向异构体选择性的化合物，并具有具有吸引力的体外ADME特性。为了验证最有希望的化合物作为高质量的化学工具，使用NanoBRET分析评估细胞靶标接合性，并在更广泛的kinome中研究选择性。最后，利用急性髓系白血病细胞模型研究了几种化合物的药理作用，从而鉴定出潜在的抗增殖药物。所报道的化合物代表了高质量的化学工具，对靶标验证研究具有潜在价值，可以作为先导优化活动的有效起点。

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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.