Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Elisa Rojas-Prats, Loreto Martinez-Gonzalez, Carmen Gil, David Ramírez, Ana Martinez
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引用次数: 0

Abstract

Cell division cycle 7 kinase (CDC7) has been found overexpressed in many cancer cell lines being also one of the kinases involved in the nuclear protein TDP-43 phosphorylation in vivo. Thus, inhibitors of CDC7 are emerging drug candidates for the treatment of oncological and neurodegenerative unmet diseases. All the known CDC7 inhibitors are ATP-competitives, lacking of selectivity enough for success in clinical trials. As allosteric sites are less conserved among kinase proteins, discovery of allosteric modulators of CDC7 is a great challenge and opportunity in this field.Using different computational approaches, we have here identified new druggable cavities on the human CDC7 structure and subsequently selective CDC7 inhibitors with allosteric modulation mainly targeting the pockets where the interaction between this kinase and its activator DBF4 takes place.

细胞分裂周期 7 (CDC7) 激酶的药腔和异位调节剂。
细胞分裂周期 7 激酶(CDC7)被发现在许多癌细胞系中过度表达,也是参与体内核蛋白 TDP-43 磷酸化的激酶之一。因此,CDC7 抑制剂是治疗肿瘤和神经退行性疾病的新兴候选药物。所有已知的 CDC7 抑制剂都是 ATP 竞争性的,缺乏足够的选择性,因此无法在临床试验中取得成功。利用不同的计算方法,我们在人类 CDC7 结构上发现了新的可药用空腔,并随后发现了具有选择性的 CDC7 抑制剂,这些抑制剂主要针对该激酶与其激活剂 DBF4 之间发生相互作用的空腔进行异构调节。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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