Description
THAL-SNS-032 is a selective CDK9 degrader PROTAC composed of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN).
Uses
THAL SNS 032 is a potent, selective and cereblon-dependent degrader of CDK9 (EC50 = 4 nM). Displays >15-fold selectivity for CDK9 over other CDKs (EC50 values are 62, 171 and 398 nM for CDK2, CDK1 and CDK7, respectively). Induces complete degradation of CDK9 at 250 nM in MOLT4 cells. Inhibits proliferation of leukemia cell lines.
Biological Activity
THAL-SNS-032, a small molecule formed by conjugating the multi-targeting kinase inhibitor SNS-032 to thalidomide, induced potent and selective degradation of CDK9 in a CRBN-dependent fashion. Treatment with THAL-SNS-032 resulted in selective degradation of CDK9 with limited effects on the protein level of other CDKs. Furthermore, THAL-SNS-032 had a prolonged pharmacodynamic effect compared with traditional kinase inhibitors. The antitumoral activity of THAL-SNS-032 in cell lines expressing ER or both ER and HER2, including luminal A cells, has been demonstrated[1-2].
References
[1] Calla M Olson. “Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation.” Nature chemical biology 14 2 (2017): 163–170.
[2] María Del Mar Noblejas-López. “Antitumoral Activity of a CDK9 PROTAC Compound in HER2-Positive Breast Cancer.” International Journal of Molecular Sciences 23 10 (2022).
