Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors

IF 2.5 4区 医学 Q3 CHEMISTRY, MEDICINAL
Jie Wei , Guochuang Zheng , Tingting Yu , Qi Liu , Wenying Yu , Cheng Jiang , Xu Quan
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引用次数: 0

Abstract

The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (5a-5h, 6a-6e, and 7a-7g) were designed, synthesized and evaluated. Among them, compound 7c was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of 7c. The good in vitro activity and promising pharmacokinetic properties indicated that the 7c was a reliable lead compound for further development.

Abstract Image

新型吡啶骨架衍生物作为CLK2/3抑制剂的发现。
CLK家族在调控转录物剪接、催化剪接体分子机制中起着至关重要的作用。它还通过磷酸化SR蛋白来调节非剪接蛋白的活性或表达。因此,clk是多种疾病,特别是肿瘤的有希望的治疗靶点。几种小分子CLK2/3抑制剂正在临床研究中,这些分子大多以含n双环杂芳基为骨架。这项工作的目标是引入一种新的骨架,并为CLK2/3抑制剂的开发提供结构多样性。本文设计、合成并评价了一系列吡啶衍生物(5a-5h、6a-6e、7a-7g)。其中化合物7c对CLK2/3和SW480肿瘤细胞的增殖均有较好的抑制作用。另外,通过小鼠药代动力学研究和稳定性试验研究了7c的给药性。7c具有良好的体外活性和良好的药动学性质,是一种值得进一步开发的先导化合物。
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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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