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CDK7 激酶抑制剂:对近年专利文献(2017-2022 年)的调查。

CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022).

机构信息

Drug Discovery and Development, Carna Biosciences, Inc, Kobe, Japan.

出版信息

Expert Opin Ther Pat. 2023 Jul-Dec;33(7-8):493-501. doi: 10.1080/13543776.2023.2262138. Epub 2023 Nov 6.

Abstract

INTRODUCTION

CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers.

AREAS COVERED

Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022.

EXPERT OPINION

Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.

摘要

简介

CDC7 是一种丝氨酸/苏氨酸激酶,在 DNA 复制中发挥重要作用。在癌细胞中抑制 CDC7 会导致致命的 S 期或 M 期进展,而在正常细胞中抑制 CDC7 不会导致细胞死亡,只会导致细胞周期在 DNA 复制检查点停滞。因此,CDC7 已被认为是癌症新型治疗干预的潜在靶点。

涵盖领域

2017 年至 2022 年期间,申报了新型小分子化合物抑制 CDC7 的专利文献。

专家意见

尽管 CDC7 作为药物靶点具有不可否认的积极影响,但作为 CDC7 抑制剂的化学结构骨架却寥寥无几。一些 CDC7 抑制剂已进入癌症治疗的临床试验,但在这些试验中并未取得令人满意的疗效。失败的一个可能原因可能是由于剂量限制毒性,并且一些观察到的毒性被认为与 CDC7 抑制无关,这表明消除不必要毒性的重要性在于确定新型化学结构骨架。另一个重要因素是患者分层,这将使更大的反应成为可能,而此类预测性生物标志物的鉴定应是开发 CDC7 抑制剂成功的关键。

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