Structural Modifications of Covalent Cathepsin S Inhibitors: Impact on Affinity, Selectivity, and Permeability

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-06-04 DOI:10.1021/acsmedchemlett.4c00050

Mergim Meta, Collin Zimmer, Natalie Fuchs, Maximilian Johannes Zecher, Albin Lahu and Tanja Schirmeister*,

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Abstract

Cathepsin S (catS) is a member of the cysteine protease family with limited tissue distribution, which is predominantly found in antigen-presenting cells. Due to overexpression and overactivity of catS in numerous cancers, inhibition of catS is supposed to improve the antitumor response. Here, we explore the potential of small-molecule catS inhibitors emphasizing their in vitro pharmacodynamics and pharmacokinetics. Membrane permeability of selected inhibitors was measured with a Parallel Artificial Membrane Permeation Assay and correlated to calculated physicochemical parameters and inhibition data. The binding kinetics and inhibition types of potent and selective new inhibitors with unexplored warheads were investigated. Our unique approach involves reversible masking of these potent warheads, allowing for further customization without compromising affinity or selectivity. The most promising inhibitors in this study include covalent aldehyde and ketone derivatives reversibly masked as hydrazones as potential candidates for therapeutic interventions targeting catalytic enzymes and modulating the immune response in cancer.

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共价 Cathepsin S 抑制剂的结构修饰：对亲和性、选择性和渗透性的影响

Cathepsin S（catS）是半胱氨酸蛋白酶家族的一员，组织分布有限，主要存在于抗原递呈细胞中。由于 catS 在许多癌症中的过度表达和过度活性，抑制 catS 可改善抗肿瘤反应。在此，我们探讨了小分子 catS 抑制剂的潜力，强调了它们的体外药效学和药代动力学。通过平行人工膜渗透试验测量了所选抑制剂的膜渗透性，并将其与计算的理化参数和抑制数据进行了关联。研究了具有未开发弹头的强效选择性新抑制剂的结合动力学和抑制类型。我们的独特方法包括对这些强效弹头进行可逆屏蔽，从而在不影响亲和性或选择性的情况下进一步定制抑制剂。这项研究中最有前景的抑制剂包括可逆掩蔽为酰肼的共价醛和酮衍生物，它们是针对催化酶和调节癌症免疫反应的治疗干预的潜在候选物质。

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.