Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer

Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone deacetylase (HDAC) was widely investigated as a novel category of anticancer drug targets due to its crucial role in various biological processes like cell-proliferation, metastasis, and apoptosis. Numerous HDAC inhibitors such as vorinostat and panobinostat are clinically approved but have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity. Therefore, HDACs with a dual targeting ability have attracted great attention. The strategy of combining a HDAC inhibitor with other antitumor agents has been proved advantageous for combating the nonselectivity and drug resistivity problems associated with single-target drugs. Henceforth, we have highlighted dual-targeting inhibitors to target HDAC along with topoisomerase, receptor tyrosine kinase inhibitors, and the zeste homolog 2 enzyme. Our Review mainly focuses on the impact of the substituent effect along with the linker variation of well-known HDAC-inhibitor-conjugated anticancer drugs.

Automated summary

Due to the multimodal character of cancer, inhibiting two targets simultaneously by a single molecule is an effective approach. Histone deacetylase (HDAC) has been investigated as a novel category of anticancer drug targets due to its crucial role. However, currently approved HDAC inhibitors have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity. Therefore, HDACs with dual targeting ability have attracted attention. Combining HDAC inhibitors with other antitumor agents has proved advantageous to combat the nonselectivity and drug resistivity problems. Our review focuses on the impact of substituent effect and linker variation of HDAC-inhibitor-conjugated anticancer drugs.