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

Abstract

The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, N-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (11b) is the most interesting compound, with IC50 values of 0.66; 1.46 and 3.67 µM. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for N-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (11d). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies.

Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study

“…Recently, a similar approach was taken by the Ramos group, this time combining CK2 and HDAC inhibition [ 124 , 125 ]. They combined the structure of vorinostat, a known selective HDAC inhibitor, with that of DMAT to create a series of dual CK2/HDAC inhibitors [ 124 ].…”

“…They combined the structure of vorinostat, a known selective HDAC inhibitor, with that of DMAT to create a series of dual CK2/HDAC inhibitors [ 124 ]. Optimisation led to the development of a series of compounds with low micromolar activity in enzymatic assays as well as low micromolar LC 50 values for a variety of cell lines ( Figure 11 ) [ 125 ]. In 2020, the same group published an alternative series of CK2/HDAC inhibitors in which the DMAT-derived portion of the compounds was replaced with the much more potent CK2 inhibitor CX-4945.…”

“…TDB and the aminoalkyl derivatives target CK2 and PIM1. DMAT/Vorinostat conjugates and 15c target CK2 and HDAC [ 121 , 123 , 125 , 126 ].…”

New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes

“…20 Since both CK2 and HDAC are involved in the related cancer-relevant biological pathways, [21][22][23][24] we anticipated that simultaneously inhibiting these two targets by a multi-target single molecule should improve efficacy compared to single-target agents. In previous publications, 25,26 we developed a series of dual CK2/HDAC1 inhibitors using TBB and DMAT as a scaffolds to promote CK2 inhibition and a hydroxamate zinc binding group (ZBG) to interact with the zinc present in the active site of HDAC1 and simulating the structure of SAHA, a potent inhibitor of HDAC1. The synthesized dual-acting agents exhibited promising inhibitory activities with the best compound showing IC50 of 5 M for both enzymes and micromolar activity in cell-based assays (Figure 2).…”

Molecular Design of Novel Chemicals for Iron Sulfide Scale Removal

“…Hydroxamates features the general formula-R(C�O)NHOH, where R could be an alkyl or aryl group. e -(C�O)NHOH moiety is the key functional group binding to iron and hence has been developed and applied in medicine in treating cardiovascular diseases, metal poisoning, and overload of iron and anticancer and antitumor agents [15][16][17][18]. Other applications are extended to corrosion inhibition, mineral floatation, and extraction of toxic metals [19,20].…”