‍Background

• Casein kinase 2 (CK2) is involved in a wide range of cellular processes such as transcription, translation, cell cycle progression, cell survival, and apoptosis.‍
• CK2 is associated with a variety of diseases including many types of cancer.
• In recent years, a number of potent CK2 inhibitors have been developed, with one of them (CX-4945) currently in Phase II clinical trials. However, these trials have been ongoing since 2010 with no reported success.
• Therefore, the development of new effective CK2 inhibitors remains a significant objective.
• The main goal of this study is the rational design of new potent CK2 inhibitors based on aurones (chemical class similar to natural and synthetic flavones).

Methodology

• The Structure-Activity Relationship (SAR) studies of flavones were utilized to guide the selection of compounds.
• Compounds were tested using an in vitro kinase assay.
• A proprietary pocket prediction algorithm was employed to refine the binding site identification.‍
• Molecular docking was performed with aurone derivatives at the ATP-binding pocket.
• ‍Lipophilic Efficiency (LipE), a parameter linking IC₅₀ and LogP values, was utilized to evaluate the effectiveness of the identified inhibitors further.

Results

• Structure of CK2, subunit alpha. ATP-binding site is shown as blue spheres.

• Strong binding of flavones with CK2 is caused by several specific interactions with the hinge region and other parts of the CK2 ATP-binding site.

• Based on the high geometric similarity between flavones and aurones, and the SAR studies of flavones, we synthesized 51 aurone derivatives.

• 43 of them were identified as hit compounds, with 6 exhibiting single-digit nanomolar activities.

• Employing LipE as a guiding parameter the property-based optimization was performed and 86 new aurone derivatives were synthesized.

• 4 of lead compounds had high activity and LipE > 4.

• IC₅₀, LogP and LipE of some known highly active CK2 inhibitors, including CX-4945 and our lead compounds are shown.