内在无序蛋白 NUPR1 抑制剂的设计：药物亲和力与靶功能的平衡,Biomolecules

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内在无序蛋白 NUPR1 抑制剂的设计：药物亲和力与靶功能的平衡
Biomolecules ( IF 4.8 ) Pub Date : 2021-10-03 , DOI: 10.3390/biom11101453
Bruno Rizzuti _{1,

2} , Wenjun Lan _{3,

4} , Patricia Santofimia-Castaño ₃ , Zhengwei Zhou ₅ , Adrián Velázquez-Campoy _{2,

6,

7,

8,

9} , Olga Abián _{2,

6,

10} , Ling Peng ₄ , José L Neira _{2,

11} , Yi Xia ₅ , Juan L Iovanna ₃

Affiliation

CNR-NANOTEC, SS Rende (CS), Department of Physics, University of Calabria, Via P. Bucci, Cubo 31 C, 87036 Rende, Cosenza, Italy.
Instituto de Biocomputación y Física de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain.
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, 13288 Marseille, France.
Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, «Equipe Labellisée Ligue Contre le Cancer», 13288 Marseille, France.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain.
Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Barcelona, Spain.
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain.
Fundacion ARAID, Government of Aragon, 50018 Zaragoza, Spain.
Instituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain.
IDIBE, Universidad Miguel Hernández, 03202 Elche, Alicante, Spain.

内在无序蛋白 (IDP) 因其生理普遍性和在包括癌症在内的各种疾病中的流行而成为有吸引力的药物靶标。NUPR1 是一种定位于整个细胞的 IDP，并参与了几种肿瘤的发展和进展。我们之前将三氟拉嗪 (TFP) 重新用作靶向 NUPR1 的药物，并通过使用基于配体的方法，从 TFP 支架开始设计药物 ZZW-115。这种衍生化合物通过阻碍 NUPR1 的核转位来阻碍小鼠胰腺导管腺癌 (PDAC) 的发展。为了进一步提高 ZZW-115 的活性，我们使用间接药物设计方法通过改变哌嗪环上的取代基来改变其化学特性。因此，我们已经合成了一系列基于相同化学支架的化合物。等温滴定量热法 (ITC) 表明，除了在烷基链末端保留与 ZZW-115 相同的化学部分的化合物外，单个亚甲基（即乙基到丙基）的长度显着增加降低了体外测量的对 NUPR1 的亲和力，而保持相同长度的烷基链并添加杂环有利于结合亲和力。然而，正如 ITC 所测量的，化合物对 NUPR1 的亲和力的小幅改进并未导致其抑制特性和纤维素功能的相应改善，正如通过测量三种不同的生物学效应所证明的那样：蛋白质核易位的阻碍，提高细胞对 NUPR1 介导的 DNA 损伤的敏感性，并防止癌细胞生长。我们的研究结果表明，成功设计针对 NUPR1 和可能的其他 IDP 的药物可能需要在有利于配体亲和力和控制蛋白质功能之间进行微妙的折衷。

"点击查看英文标题和摘要"

Design of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function

Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs.

更新日期：2021-10-03

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