Strategic Design and Development of Indole-Based Compounds as Potent malic Enzyme 3 Inhibitors for Pancreatic Tumor Therapy.

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-09-14 DOI:10.1002/cmdc.202500470

Gaurav Sheth, Shailesh R Shah, Prabal Sengupta, Tushar Jarag, Sabbirhusen Chimanwala, Kalapatapu V V M Sairam, Vaibhav Jain, Rashmi Talwar, Avinash Dhanave, Mehul Raviya, Harendra Jha, Rajasekhar Reddy Chilakala, Trinadha Rao Chitturi

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Abstract

Malic enzyme 3 (ME3) plays a critical role in the survival of SMAD4^-/-/ME2^-/- pancreatic ductal adenocarcinoma (PDAC) cells by supporting energy production and maintaining redox homeostasis. Therefore, targeting ME3 with small-molecule inhibitors presents a promising therapeutic strategy for PDAC patients with SMAD4/ME2 deletions. Building upon our previously developed ME3 inhibitor, a systematic exploration of the structure-activity relationship (SAR) was undertaken to identify novel chemotypes. This effort led to the discovery of a new series of indole-substituted piperazine carboxamides with potent ME3 inhibitory activity, among which compound 13 emerged to be the most effective in PDAC cell lines. Furthermore, the synergistic effects of the newly identified compound 13 with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib were evaluated on Hs766T cells which revealed a significant synergism of this combination.

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吲哚类化合物作为有效的苹果酸酶3抑制剂用于胰腺肿瘤治疗的策略设计和开发。

苹果酸酶3 （ME3）通过支持能量产生和维持氧化还原稳态，在SMAD4-/-/ME2-/-胰腺导管腺癌（PDAC）细胞的存活中起关键作用。因此，用小分子抑制剂靶向ME3为SMAD4/ME2缺失的PDAC患者提供了一种有希望的治疗策略。在我们之前开发的ME3抑制剂的基础上，对结构-活性关系（SAR）进行了系统的探索，以确定新的化学型。这一努力导致发现了一系列具有强ME3抑制活性的吲哚取代哌嗪carboxamide，其中化合物13在PDAC细胞系中最有效。此外，新鉴定的化合物13与丝裂原活化蛋白激酶（MEK）抑制剂trametinib对Hs766T细胞的增效作用进行了评估，结果显示该组合具有显著的增效作用。

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

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

期刊介绍： Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.