CDK2 Allosteric Modulators: The New Route in the Design of New Drugs as Anticancer and Non-hormonal Contraceptives.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Current medicinal chemistry Pub Date : 2025-01-07 DOI:10.2174/0109298673331207241019085108
Giulia Culletta, Anna Maria Almerico, Marco Tutone
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Abstract

CDK2 plays a pivotal role in controlling the cell cycle progression in eukaryotes and for this reason, it has been the subject of several studies for suitable inhibitors in the last decades. But more than 30 years of basic research have not generated an inhibitor as marketed drugs. Some inhibitors are to date in early phase clinical development. Moreover, most efforts to develop CDK2 inhibitors have been oriented towards orthosteric inhibitors, which block the kinase activity by binding to the ATP binding site, competing directly with ATP. These compounds have off-target kinase activity, because of the structural homology of the active sites of several other kinases. Targeting the CDK2 allosteric binding pocket could produce successful CDK2 inhibitors. Few examples of high-affinity allosteric CDK2 inhibitors are known. Despite promising research results, none has been approved for marketing. In recent years, various methodologies have been reported capable of identifying new and never-discovered portions of the target protein, which present adequate druggability characteristics. In this paper, we have highlighted and discussed the more recent findings on allosteric inhibitors intending to encouraging further exploration mainly focused on in silico drug discovery.

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CDK2变构调节剂:抗癌和非激素避孕药新药设计的新途径。
在真核生物中,CDK2在控制细胞周期进程中起着关键作用,因此,在过去的几十年里,它一直是寻找合适抑制剂的几项研究的主题。但是30多年的基础研究还没有产生一种抑制剂作为上市药物。一些抑制剂目前处于早期临床开发阶段。此外,开发CDK2抑制剂的大多数努力都是面向正位抑制剂,它通过与ATP结合位点结合来阻断激酶活性,直接与ATP竞争。这些化合物具有脱靶激酶活性,因为其结构与其他几种激酶的活性位点同源。靶向CDK2变构结合袋可成功制备CDK2抑制剂。已知的高亲和力变构CDK2抑制剂的例子很少。尽管研究结果很有希望,但没有一种被批准上市。近年来,各种方法已经被报道能够识别新的和从未发现的目标蛋白部分,这些部分具有足够的药物特性。在本文中,我们强调并讨论了关于变构抑制剂的最新发现,旨在鼓励进一步的探索,主要集中在硅药物的发现上。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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