Harnessing the cyclization strategy for new drug discovery.
Harnessing the cyclization strategy for new drug discovery.
复制标题
利用环化策略进行新药发现
DOI：
10.1016/j.apsb.2022.09.022
复制
发表时间：
2022-12
影响因子：
14.5
通讯作者：
Yu, Bin
中科院分区：
文献类型：
--
作者：
Tang, Kai;Wang, Shu;Gao, Wenshuo;Song, Yihui;Yu, Bin
关键词：
设计对目标靶点具有高亲和力和特异性的新配体一直是药物发现的中心焦点。作为药物发现中最常用的方法之一，环化是通过增加结构新奇、支架多样性和复杂性来鉴定新的先导化合物的可行策略。这种策略也可能用于后续的药物发现，而不会侵犯专利。近年来，环化策略在发现针对不同靶点治疗各种疾病的新先导化合物方面取得了巨大成功。在此，我们首先简要总结了环化策略在发现新的小分子先导化合物，包括蛋白水解靶向嵌合体（PROTAC）分子中的应用。特别是，我们专注于四个主要的策略，包括稠环环化，链状环化，螺环化和大环化，并强调使用的环化策略在铅的产生。最后，包括合成的棘手性，相对较差的药代动力学（PK）曲线和缺乏合理的结构为基础的环化的结构信息的挑战也进行了简要讨论。我们希望这篇综述，虽然不是详尽的，但可以为发现新的先导化合物的环化策略提供及时的概述。环化反应是一种很有前途的新药发现策略。
The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery. As one of the most commonly used methods in drug discovery, the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty, scaffold diversity and complexity. Such strategy could also be potentially used for the follow-on drug discovery without patent infringement. In recent years, the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases. Herein, we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds, including the proteolysis targeting chimeras (PROTAC) molecules. Particularly, we focus on four main strategies including fused ring cyclization, chain cyclization, spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation. Finally, the challenges including the synthetic intractability, relatively poor pharmacokinetics (PK) profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed. We hope this review, not exhaustive, could provide a timely overview on the cyclization strategy for the discovery of new lead compounds. The cyclization represents a promising strategy for new drug discovery.
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DOI：
10.1158/1078-0432.ccr-16-2071
发表时间：
2017-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cardenas MG;Oswald E;Yu W;Xue F;MacKerell AD Jr;Melnick AM
通讯作者：
Melnick AM
LSD1 作为生物标志物及其抑制剂的临床试验结果：肿瘤的治疗机会
影响因子：
--
作者：
Agboyibor C;Dong J;Effah CY;Drokow EK;Pervaiz W;Liu HM
通讯作者：
Liu HM
影响因子：
6.7
作者：
Chaal BK;Gupta AP;Wastuwidyaningtyas BD;Luah YH;Bozdech Z
通讯作者：
Bozdech Z
影响因子：
7.3
作者：
Dai, Xing-Jie;Liu, Ying;Liu, Hong-Min
通讯作者：
Liu, Hong-Min
影响因子：
2.7
作者：
Cheng, Ming-Fu;Hung, Ming-Shiu;Ueng, Shau-Hua
通讯作者：
Ueng, Shau-Hua