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用于肺部局部受限蛋白质降解的局部 BET 蛋白降解靶向嵌合体

Topical BET PROTACs for locally restricted protein degradation in the lung.

作者信息

Hemmerling Martin, Liu Jianming, Piras Antonio, Pehrson Rikard, Hedström Ulf, Cassani Carlo, Ranieri Beatrice, Kwapień Karolina, Ribbing Karin, Forss Cecilia, Slettengren Oliwia, Eisele Frederik, Ding Mei, Hansson Pia, Novén Anna, Nordberg Markus, Park Hyunsoo, Jarke Annica, Rosenbaum Lisa-Catherine, Malmberg Jesper, Borde Annika, Badolo Lassina, Engsevi Madeleine, Jirholt Johan, Breccia Perla, Schiesser Stefan, Ripa Lena, Czechtizky Werngard

机构信息

Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden

Assays, Profiling & Cell Science, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca Gothenburg Sweden.

出版信息

RSC Med Chem. 2025 Apr 21. doi: 10.1039/d5md00173k.

Abstract

Proteolysis targeting chimeras (PROTACs) have been studied extensively to optimize their oral bioavailability. Based on Lipinski's and Veber's rules, molecular weight, log , log , the number of hydrogen bond donors and acceptors, the polar surface area and the number of rotatable bonds play a critical role for the oral bioavailability of any given PROTAC. Multiple analyses of the published PROTAC chemical space show that the overall guidelines for obtaining orally available PROTACs are broadly in line with those of the bRo5 space established for oral drugs. In contrast to the significant knowledge that has been generated for the design of oral PROTACs, there is little expertise regarding inhaled and generally topically administered PROTACs. In this work we (1) introduce parameters influencing the inhaled route of administration of PROTACs and (2) describe the first examples of inhaled bromodomain and extra terminal domain (BET) PROTACs which were designed for inhaled delivery and characterized and .

摘要

靶向蛋白降解嵌合体(PROTAC)已被广泛研究以优化其口服生物利用度。基于Lipinski规则和Veber规则,分子量、logP、logD、氢键供体和受体的数量、极性表面积以及可旋转键的数量对任何给定PROTAC的口服生物利用度起着关键作用。对已发表的PROTAC化学空间的多项分析表明,获得口服可用PROTAC的总体指导原则与为口服药物建立的bRo5空间的指导原则大致一致。与在口服PROTAC设计方面已积累的大量知识形成对比的是,关于吸入和一般局部给药的PROTAC的专业知识很少。在这项工作中,我们(1)介绍了影响PROTAC吸入给药途径的参数,(2)描述了首批为吸入给药设计并进行了表征的吸入型溴结构域和额外末端结构域(BET)PROTAC实例。

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本文引用的文献

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