Novel non-ATP competitive small molecules targeting the CK2 alpha/beta interface

作者：Brear Paul; North Andrew; Iegre Jessica; Georgiou Kathy Hadje; Lubin Alexandra; Carro Laura; Green William; Sore Hannah F; Hyvonen Marko; Spring David R^*

来源：Bioorganic & Medicinal Chemistry, 2018, 26(11): 3016-3020.

DOI：10.1016/j.bmc.2018.05.011

• CK2
• Protein-protein interaction
• Fragment based drug discovery

Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2 alpha and CK2 beta at the alpha-beta interface of the holoenzyme. A fragment, CAM187, with an IC50 of 44 mu M and a molecular weight of only 257 gmol(-1) has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2 alpha. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation.

• 出版日期2018-7-15