CDKs (Cyclin-dependent kinases) are serine-threonine kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. There are around 20 Cyclin-dependent kinases (CDK1-20) known till date. CDK1, 4 and 5 are involved in cell cycle, and CDK7, 8, 9 and 11 are associated with transcription. Among them, CDK7 is an enzyme that in humans is encoded by the CDK7 gene.
One unique point of CDK7 is that CDK7 plays dual role in both regulating the cell cycle and the transcriptional regulation. This protein forms a trimeric complex with cyclin H and MAT1, which functions as a Cdk-activating kinase (CAK). It is an essential component of the transcription factor TFIIH, that is involved in transcription initiation and DNA repair. This protein is thought to serve as a direct link between the regulation of transcription and the cell cycle. Since the small molecule of CDK4/6 inhibitors have provided great clinical success in this family, many other CDK inhibitors are also deeply investigated. Several CDK7 small molecule inhibitors have been developed.
SHR5428 is a potent, orally active, selective and noncovalent CDK7 inhibitor.
Meanwhile, SHR5428 shows high selectivity over CDK1, CDK2, CDK4, CDK6, CDK9, CDK12 in CDK family. In addition, it potently inhibits CDK7 enzymatic activity and triple negative breast cancer cellular activity on MDA-MB-468 cell. Importantly, SHR5428 also displays favorable pharmacokinetic properties in different preclinical species such as mouse, rat and dog. In a HCC70 cell line derived xenograft NDG mouse model, SHR5428 (3, 10 and 30 mg/kg) shows potent inhibitory effect on tumor growth in a dose-dependent manner. Moreover, SHR5428 does not affect mouse body weight. Thus, SHR5428 has the potential for the breast cancer research.
In conclusion, SHR5428 is an orally active, selective and noncovalent CDK7 inhibitor with anticancer effects.
References:
[1] Jia M, et al. Bioorg Med Chem Lett. 2023 Sep 1;93:129429.