Structural insights for producing CK2α1-specific inhibitors

Casein kinase 2 catalytic subunit (CK2 alpha) is classified into two subtypes CK2 alpha 1 and CK2 alpha 2. CK2 alpha 1 is a drug discovery target, whereas CK2 alpha 2 is an off-target of CK2 alpha 1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2 alpha 1. Hematein was identified previously as a non-ATP-competitive inhibitor for CK2 alpha 1, whereas this compound acts as an ATP competitive CK2 alpha 2 inhibitor. Crystal structures of CK2 alpha 1 and CK2 alpha 2 in complex with hematein revealed distinct binding features that provide structural insights for producing CK2 alpha 1-selective inhibitors.