Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer

Abstract

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.

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

“…Based on the earlier findings, the designed dual HDAC/EGFR inhibitors acquire the following pharmacophoric features: (a) 2methylquinazoline main scaffold acting as a capping group in HDAC inhibitors and to occupy the ATP binding site for EGFR inhibition, (b) phenoxy moiety acts as a linker for HDAC inhibition and to occupy the hinge region of EGFR, (c) chalcone moiety which could act as a common ZBG for HDAC inhibition and may offer an additional binding interaction for inhibition of EGFR enzyme and, otherwise their powerful role in induction of apoptosis, and (d) hydrophobic tail to occupy the hydrophobic pocket of EGFR. [31,40] Employing molecular hybridization to connect the 2-methylquinazoline and chalcone moieties through an oxygen linker, compounds 5a-e were designed to act as dual inhibitors for HDAC and EGFR TK.…”

“…[ 54–56 ] The study demonstrated that merging quinazoline core with ZBGs via a suitable linker could surmount tumor relapse and drug resistance. [ 35,57 ] HDAC/EGFR dual inhibitors with the aim of discovering potent antitumor agents showed promising results in combating the nonselectivity and drug resistance problems associated with single‐target drugs. [ 31 ]…”

“…[29,30] Also, the recently researched tucidinostat (IV) is used as a treatment for pancreatic cancer (Figure 1). [31] A typical HDAC inhibitor comprises a capping group, a zinc-binding group (ZBG), and a suitable linker. There are a variety of traditional ZBGs for HDAC inhibitors, such as hydroxamic acids, carboxylates, aminobenzamides, and so on.…”

“…[35,57] HDAC/EGFR dual inhibitors with the aim of discovering potent antitumor agents showed promising results in combating the nonselectivity and drug resistance problems associated with single-target drugs. [31] Moreover, chalcone is an α,β-unsaturated ketone that serves as a fundamental structure for numerous important bioactive compounds with a wide range of biological functions, particularly as anticancer agents. [58][59][60] Modifying the structure of chalcones proved to be an effective approach for developing novel anticancer drugs with different levels of effectiveness and modes of action.…”

Platinum(iv) combo prodrugs containing cyclohexane-1R,2R-diamine, valproic acid, and perillic acid as a multiaction chemotherapeutic platform for colon cancer

“…Noticeably, normal cells are usually more resistant than tumor cells to HDACIs. [24][25][26][27] The combination of HDACIs as chemosensitizers with other cancer therapeutics has shown great potential in preclinical and therefore clinical trials and may represent a way to achieve complete therapeutic benefits. [28][29][30][31][32] Different HDAC inhibitors have already been linked in the axial positions of Pt(IV) cores, showing synergistic activity with Pt(II) metabolites.…”