Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors

Area of Science:

• Medicinal Chemistry
• Drug Design
• Oncology

Background:

• Multitarget drugs (MTDs) offer innovative therapeutic strategies for complex diseases like cancer.
• Targeting histone deacetylase (HDAC) and protein kinase CK2 simultaneously presents a novel approach for cancer treatment.

Purpose of the Study:

• To design and synthesize novel multitarget inhibitors targeting both HDAC and CK2 enzymes.
• To evaluate the in vitro and cellular efficacy of these novel compounds as potential anti-cancer agents.

Main Methods:

• Utilized tetrabromobenzotriazole (TBB) and DMAT scaffolds for CK2 inhibition.
• Incorporated a hydroxamate group (zinc binding group, ZBG) for HDAC active site coordination.
• Synthesized and characterized new multitarget inhibitors, followed by in vitro and cellular assays.

Main Results:

• Compound 11b demonstrated potent in vitro inhibition of HDAC6, HDAC1, and CK2 with IC50 values in the low micromolar range.
• Compound 11d exhibited significant cytotoxic activity, proapoptotic effects, and favorable mitochondria-targeting properties in cancer cell lines.
• Compound 11d also displayed multidrug-circumventing capabilities, indicating its potential for overcoming drug resistance.

Conclusions:

• The designed multitarget inhibitors, particularly compound 11d, show significant promise as novel anti-cancer therapeutics.
• Compound 11d is identified as a strong drug candidate for further preclinical evaluation in vivo.
• This study highlights the potential of dual HDAC and CK2 inhibition as a viable strategy in cancer therapy.