Discovery of MK-2118, a Small-Molecule Agonist of STING

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2026-07-09 Epub Date: 2026-06-11 DOI:10.1021/acsmedchemlett.5c00540

Timothy Henderson*, Michael D. Altman, Alexei V. Buevich, Brandon Cash, Saso Cemerski, Wonsuk Chang, Yiping Chen, Matthew Childers, Jared Cumming, Peter J. Dandliker, Guo Feng, Andrew Haidle, Robert P. Hayes, Thu Ho, James P. Jewell, Ilona Kariv, Ian Knemeyer, Johnny Kopinja, Brian M. Lacey, Jason Laskey, Charles A. Lesburg, Rui Liang, Jongwon Lim, Brian J. Long, Min Lu, Yanhong Ma, Ellen C. Minnihan, Ryan D. Otte, Gregory O’Donnell, Bo-Sheng Pan, Samanthi A. Perera, Jennifer A. Piesvaux, Jeremy P. Presland, Laura Price, Larissa Rakhilina, Berengere Sauvagnat, Gottfried K. Schroeder, Sharad Sharma, B. Wesley Trotter, Sriram Tyagarajan, Hyun Woo, Daniel F. Wyss, Serena Xu, George H. Addona and David Jonathan Bennett,

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Abstract

Agonists of Stimulator of Interferon Genes (STING) have the potential to activate the innate and adaptive immune system for cancer treatment. Early efforts in identifying suitable therapeutics were focused on cyclic dinucleotide (CDN) analogs of 2′,3′-cGAMP, the endogenous ligand to STING. CDNs lack of tractable bioavailability led us to consider small-molecule modulators of STING. We previously reported the identification of MSA-2, an orally available non-nucleotide STING agonist with antitumor activity. Optimization efforts in this series faced challenges with uniform activity across species, cell shift, and steep structure activity relationships. Herein we report lead optimization efforts guided by structure-based drug design to identify the MSA-2 analog MK-2118.

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STING小分子激动剂MK-2118的发现

干扰素基因刺激因子激动剂（STING）具有激活先天性和适应性免疫系统的潜力，可用于癌症治疗。早期寻找合适治疗方法的努力主要集中在2 ',3 ' -cGAMP （STING的内源性配体）的环二核苷酸（CDN）类似物上。cdn缺乏可处理的生物利用度，这促使我们考虑STING的小分子调节剂。我们之前报道了MSA-2的鉴定，这是一种口服的非核苷酸STING激动剂，具有抗肿瘤活性。本系列的优化工作面临着跨物种、细胞移位和陡峭的结构活性关系的统一活性的挑战。在此，我们报告了基于结构的药物设计指导下的先导优化工作，以识别MSA-2类似物MK-2118。

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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.