Auristatin S: An Auristatin Payload with Improved Tolerability and Modified Bystander Activity.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-23 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00238

Philip N Moquist, Nicole M-L Eng-Duncan, Tim D Bovee, Katie Snead, Lauren Bou, Xinqun Zhang, Brittney Blackburn, Jennifer Wright, Jessica K Simmons, Haley D Neff-LaFord, Peter D Senter, Svetlana O Doronina

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引用次数: 0

Abstract

Auristatins are a class of antibody-drug conjugate (ADC) payloads employed in anticancer therapies. Auristatin payloads are clinically validated and effective, but opportunities remain to improve their clinical benefit. Here, we describe the development and characterization of a new auristatin payload, Auristatin S, that demonstrates robust efficacy and improved off-target toxicity. This effort focused on the optimization of bystander activity, which is a key property that modulates the efficacy and tolerability of the ADC payloads. In vitro screening of tubulin binding, free drug cytotoxicity, and ADC activity were utilized to characterize the bystander activity profile. The corresponding peptide-linked conjugates showed excellent on-target cytotoxicity against cancer cells and induction of immunogenic cell death. Tolerability of Auristatin S was improved relative to historical controls, and in vivo activity and bystander activity were confirmed in a Karpas/KarpasBVR model.

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Auristatin S：一种具有改进耐受性和改进旁观者活动的Auristatin载荷。

Auristatins是一类用于抗癌治疗的抗体-药物偶联（ADC）有效载荷。耳抑素有效载荷在临床得到了验证和有效，但仍有机会提高其临床效益。在这里，我们描述了一种新的auristatin有效载荷的开发和表征，auristatin S显示出强大的功效和改善的脱靶毒性。这项工作的重点是旁观者活动的优化，这是调节ADC有效载荷的有效性和耐受性的关键特性。体外筛选微管蛋白结合、游离药物细胞毒性和ADC活性来表征旁观者活性谱。相应的肽连接偶联物对癌细胞表现出优异的靶向细胞毒性和诱导免疫原性细胞死亡。与历史对照相比，Auristatin S的耐受性得到了改善，并且在Karpas/KarpasBVR模型中证实了体内活性和旁观者活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.