YKL-5-124 is a Selective, Irreversible and Covalent CDK7 Inhibitor
Posted On 2020-08-26
Cyclin-dependent kinase 7 (CDK7) is a member of the cyclin-dependent protein kinase (CDK) family. Specifically, CDK7 is an important component of TFIIH, which is involved in transcription initiation and DNA repair. Besides, CDK7 protein is a direct link between transcriptional regulation and cell cycle. In the cytoplasm, CDK7 contains the core of CDK activated kinase (CAK). Moreover, CAK is a trimeric complex, which also contains CDK7 specific binding chaperones, cyclin H, and MAT1. Inhibition of CDK7 resulted in the accumulation of G1 or G2/M cells and a decrease in the number of S-phase cells. And this indicates that CDK7 kinase activity is required for cell proliferation. Furthermore, CDK7 can also activate transcription by recruitment of blocking enzymes, regulating the deposition of histone markers related to active transcription and suspending induction. YKL-5-124 is a potent, selective, irreversible, and covalent CDK7 inhibitor.
YKL-5-124 is a potent, selective, irreversible and covalent CDK7 inhibitor.
Let’s study the specific role of the CDK7 inhibitor, YKL-5-124. First of all, YKL-5-124 is a CDK7 inhibitor with IC50s of 53.5 nM and 9.7 nM for CDK7 and CDK7/Mat1/CycH, respectively. Meanwhile, YKL-5-124 is >100-fold greater selective for CDK7 than CDK9 and CDK2, and inactive against CDK12 and CDK13. Nonetheless, YKL-5-124 induces a strong cell-cycle arrest, inhibits E2F-driven gene expression, and exhibits little effect on RNA polymerase II phosphorylation status.
In the second place, YKL-5-124 (0-2000 nM) treatment causes a dose-dependent increase in G1- and G2/M-phase cells and a corresponding loss of S-phase cells. Importantly, YKL-5-124 inhibits CDK1 T-loop phosphorylation, and to a lesser extent CDK2 T-loop phosphorylation in a concentration-dependent fashion. Particularly, YKL-5-124 acts as a competitor at a concentration of about 30 nM that blocks the pull-down of CDK7-cyclin H. Interestingly, YKL-5-124 has no effect on the pull-down of cyclin K-CDK12/13 in HAP1 cells. Treatment with 100 nM YKL-5-124 reduces CDK7-cyclin H binding to bioTHZ1 by >50% at 30 min.
All in all, YKL-5-124 is a potent, selective, irreversible and covalent CDK7 inhibitor.
Olson CM, et al. 2019 Jun 20;26(6):792-803.e10.