Targeting Human Protein Kinase CK2 by a Library of Indeno[1,2‐ b ]Indoles: Contribution of Thermal Shift Assay to Pre‐Screening and Co‐Crystallization to Post‐Screening

ABSTRACT

Protein kinase CK2 is the subject of numerous studies in medicinal chemistry due to its involvement in the development of several diseases, primarily cancers. Its overexpression in tumor cells is related to key processes such as tumor immune evasion and cell proliferation. The scientific approach of this study aims to investigate the thermal shift assay (TSA) as a pre‐screening tool and to complement it with a co‐crystallization approach in post‐screening. Therefore, the synthesis of seven small‐molecule CK2 inhibitors derived from indeno[1,2‐ b ]indoles was supplemented by 18 related derivatives from our in‐house compound library. The 25 molecules belong to four sub‐scaffolds, namely 4 b ,9 b ‐dihydroxy‐4 b ,5,6,7,8,9 b ‐hexahydroindeno[1,2‐ b ]indole‐9,10‐dione (D‐0), 5,6,7,8‐tetrahydroindeno[1,2‐ b ]indole‐9,10‐dione (D‐1), 9‐hydroxy‐5 H ‐indeno[1,2‐ b ]indol‐10‐one (D‐2), and 5 H ‐indeno[1,2‐ b ]indole‐6,9,10‐trione (D‐3). The most active CK2 inhibitors identified by capillary electrophoresis (CE)‐based assay belong to the D‐1 sub‐scaffold. In the TSA, these compounds also generate significant shifts of the melting temperature (Tm) of CK2, indicating a clear correlation between the results of the CE‐based assay and those of the TSA. The contribution of co‐crystallization in post‐screening also demonstrated the effectiveness of D‐1 sub‐scaffold compared with D‐0 sub‐scaffold.