药物发现
DNA修复
合成致死
DNA损伤
药物开发
生物
计算生物学
化学
药品
癌症研究
生物信息学
遗传学
DNA
药理学
作者
Peng Lei,Jifa Zhang,Peiyu Liao,Changyu Ren,Jiaxing Wang,Yuxi Wang
标识
DOI:10.1016/j.ejmech.2022.114603
摘要
CDK12 is a cyclin-dependent kinase that plays critical roles in DNA replication, transcription, mRNA splicing, and DNA damage repair. CDK12 genomic changes, including mutation, amplification, deletion, and fusion, lead to various cancers, such as colorectal cancer, gastric cancer, and ovarian cancer. An increasing number of CDK12 inhibitors have been reported since CDK12 was identified as a biomarker and cancer therapeutic target. A major challenge lies in that CDK12 and CDK13 share highly similar sequences, which leads to great difficulties in the development of highly selective CDK12 inhibitors. In recent years, great efforts were made in developing selective CDK12 blockers. Techniques including PROTAC and molecular glue degraders were also applied to facilitate their development. Also, the drug combination strategy of CDK12 small molecule inhibitors were studied. This review discusses the latest studies on CDK12 inhibitors and analyzes their structure-activity relationships, shedding light on their further development.
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