Toward Tumor-Conditional Release of Histone Deacetylase Inhibitors from Nongenotoxic Drug Conjugates

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-18 DOI:10.1021/acsmedchemlett.6c00312

Ryan K. Muir, Ryan Gonciarz, Veronica Steri, Brian R. Blank, Byron Hahn, Adam R. Renslo

引用次数: 0

Abstract

Inhibition of histone deacetylase (HDAC) metalloenzymes with hydroxamic acid-based inhibitors is compromised by generally poor metalloenzyme selectivity and the potential for genotoxicity arising from isocyanate metabolites. Here, we applied our previously described platform for iron(II)-activatable drug delivery to the pan-HDAC inhibitor panobinostat and its study in multiple myeloma cell line models. We demonstrate successful caging of HDAC activity in conjugate form, as well as mitigation of genotoxicity in a bioisosteric control. Finally, we identify the carboxy esterase CES1 as being responsible for unexpected proteolytic instability of the panobinostat conjugate in vitro and in vivo, identifying a focus for future work toward the ultimate goal of mitigating hydroxamate toxicity and mutagenicity through tumor-conditional activation.

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非基因毒性药物偶联物中组蛋白去乙酰化酶抑制剂的肿瘤条件释放

以羟基酸为基础的抑制剂抑制组蛋白去乙酰化酶（HDAC）金属酶，由于金属酶的选择性一般较差，并且异氰酸盐代谢物可能产生遗传毒性。在这里，我们将我们之前描述的铁（II）可激活药物递送平台应用于泛hdac抑制剂panobinostata及其在多发性骨髓瘤细胞系模型中的研究。我们成功地证明了HDAC在共轭形式下的活性，以及在生物等压控制下的遗传毒性的减轻。最后，我们发现羧基酯酶CES1在体外和体内导致了panobinostat偶联物意想不到的蛋白水解不稳定性，确定了未来工作的重点，最终目标是通过肿瘤条件激活减轻羟基毒性和致突变性。

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.