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In this work, we have synthesized a set of peptoid-based histone deacetylase inhibitors (HDACi) with a substituted hydrazide moiety as zinc-binding group. Subsequently, all compounds were evaluated in biochemical HDAC inhibition assays and for their antiproliferative activity against native and cisplatin-resistant cancer cell lines. The hydrazide derivatives with a propyl or butyl substituent (compounds 5 and 6 ) emerged as the most potent class I HDAC selective inhibitors (HDAC1-3). Further, compounds 5 and 6 outperformed entinostat in cytotoxicity assays and were able to reverse chemoresistance in cisplatin-resistant A2780 (ovarian) and Cal27 (head-neck) cancer cell lines. Moreover, the hydrazide derivatives 5 and 6 showed strong synergism with cisplatin (combination indices <0.2), again outperforming entinostat, and increased DNA damage, p21, and pro-apoptotic BIM expression, leading to caspase-mediated apoptosis and cell death. Thus, compounds 5 and 6 represent promising lead structures for developing new HDACi capable of reversing chemoresistance in cisplatin resistant cancer cells.

Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium of hydroxamic acids was generated and evaluated for in vitro cytotoxicity against HCT-116 cells (human colorectal cancer cell lines). The most potent cell growth inhibitor 2 (GI 50 = 0.495 μMm HCT-116 cells) shows promising anticancer effects by reducing colony formation and inducing cell cycle arrest in HCT-116 cells. It exhibits preferential inhibition of HDAC6, along with potent inhibition of LSD1 compared to standard inhibitors. Moreover, Compound 2 upregulates acetyl-tubulin, acetyl-histone H3, and H3K4me2, indicative of LSD1 and HDAC inhibition. In vivo , it demonstrates significant antitumor activity against colorectal cancer, better than irinotecan, and effectively inhibits growth in patient-derived CRC organoids.

Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC 50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC 50 of 3.6 µM on neuroblastoma cells., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound ( R ) - 23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of ( R ) - 23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, ( R ) - 23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor ( R ) - 23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.

Cancer is one of the primary causes of mortality worldwide. Despite nowadays are numerous therapeutic treatments to fight tumor progression, it is still challenging to completely overcome it. It is known that Histone Deacetylases (HDACs), epigenetic enzymes that remove acetyl groups from lysines on histone's tails, are overexpressed in various types of cancer, and their inhibition represents a valid therapeutic strategy. To date, some HDAC inhibitors have achieved FDA approval. Nevertheless, several other potential drug candidates have been developed. This review aims primarily to be comprehensive of the studies done so far regarding HDAC inhibitors bearing heterocyclic rings since their therapeutic potential is well known and has gained increasing interest in recent years. Hence, inserting heterocyclic moieties in the HDAC-inhibiting scaffold can be a valuable strategy to provide potent and/or selective compounds. Here, in addition to summarizing the properties of novel heterocyclic HDAC inhibiting compounds, we also provide ideas for developing new, more potent, and selective compounds for treating cancer., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying HL-5s with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, HL-5s induces ferroptosis by augmenting LPO production. Mechanistically, HL-5s increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, HL-5s not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and HL-5s may serve as a promising candidate for future cancer treatment.

HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC 50 = 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k , demonstrated remarkable inhibitory potency against HDAC8 (IC 50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC 50 = 89 nM) and remarkable PD-L1-degrading activity (DC 50 = 5.7 μM, D max = 80% at 10 μM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3 + CD4 + helper T and CD3 + CD8 + cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD 50 > 1000 mg/kg) and favorable pharmacokinetic properties ( F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

Synergetic inhibition of FMS-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) by small molecule chimera presents a promising therapeutic approach for acute myeloid leukemia (AML) with FLT3 mutations. In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Then, we employed a pharmacophore fusion strategy to develop a novel series of FLT3/HDAC dual inhibitors. Among them, compound 25h demonstrated superior inhibitory activity against both FLT3 and HDAC. In particular, compound 25h exhibited enhanced anti-proliferation activity against MOLM-13 cells in comparison to gilteritinib, vorinostat, and their combination, while maintaining reduced cytotoxicity towards normal cells. Mechanistically, the heightened anti-tumor effect of compound 25h was attributed to its more potent regulation of intracellular pathways, notably phosphorylation of ERK, compared to single drug and combination treatments. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aim: Chemotherapy has been well shown to enhance life expectancy in patients with malignancy. However, conventional chemotherapy drugs, particularly cisplatin, are highly associated with nephrotoxicity, which limits therapeutic efficacy and impairs quality of life. Histone deacetylases (HDACs) are proteases that play significant roles in diseases by influencing protein post-translational modification and gene expression. Agents that inhibit HDAC enzymes have been developed and approved by the FDA as anticancer drugs. It is worth noting that in certain preclinical studies with tumour cell lines, the integration of HDAC modulators and cisplatin not only exerts synergistic or additive tumour-killing effects but also alleviates cisplatin nephrotoxicity. The aim of this review is to discuss the role of HDACs in cisplatin nephrotoxicity., Methods: After searching in PubMed and Web of Science databases using 'Histone deacetylase', 'nephrotoxicity', 'cisplatin', and 'onconpehrology' as keywords, studies related was compiled and examined., Results: HDAC inhibitors exert renal protective effects by inhibiting inflammation, apoptosis, oxidative stress, and promoting autophagy; whereas sirtuins play a renal protective role by regulating lipid metabolism, inhibiting inflammation and apoptosis, and protecting mitochondrial biosynthesis and mitochondrial dynamics. These potential interactions provide clues concerning targets for molecular treatment., Conclusion: This review encapsulates the function and molecular mechanisms of HDACs in cisplatin nephrotoxicity, providing the current view by which HDACs induce different biological signaling in the regulation of chemotherapy-associated renal injury. More importantly, this review exhaustively elucidates that HDACs could be targeted to develop a new therapeutic strategy in treating cisplatin nephrotoxicity, which will extend the knowledge of the biological impact and clinical implications of HDACs.

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[ d ][1, 3 ]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5- a ]pyridin-2-yl)amino)methyl)- N -hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC 50 values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho -phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f . Compared to LH4f , most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC 50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cancer has been a leading cause of death over the last few decades in western countries as well as in Taiwan. However, traditional therapies are limited by the adverse effects of chemotherapy and radiotherapy, and tumor recurrence may occur. Therefore, it is critical to develop novel therapeutic drugs. In the field of HDAC inhibitor development, apart from the hydroxamic acid moiety, 2-aminobenzamide also functions as a zinc-binding domain, which is shown in well-known HDAC inhibitors such as Entinostat and Chidamide. With recent successful experiences in synthesizing 1-(phenylsulfonyl)indole-based compounds, in this study, we further combined two features of the above chemical compounds and generated indolyl benzamides. Compounds were screened in different cancer cell lines, and enzyme activity was examined to demonstrate their potential for anti-HDAC activity. Various biological functional assays evidenced that two of these compounds could suppress cancer growth and migration capacity, through regulating epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis mechanisms. Data from 3D cancer cells and the in vivo zebrafish model suggested the potential of these compounds in cancer therapy in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets., (© 2024 John Wiley & Sons Ltd.)

In modern cancer therapy, blockage of more than one target is a standard approach, and there are already many dual-target drugs that can achieve multiple inhibition through a single molecule. Herein, we designed and synthesized a series of novel derivatives with signal transducer and activator of transcription 3 (STAT3) and histone deacetylase (HDAC) inhibitory activity through strategy of combining pharmacophore based on the STAT3 inhibitor E28 and HDAC inhibitor MS-275. Among them, compound 24 (IC 50  = 8.22 ± 0.27 μM) showed better anti-tumor activity than the clinical Class I HDAC inhibitor MS-275 (IC 50  = 14.65 ± 0.24 μM) in MCF-7 breast cancer cells. Furthermore, the dual inhibition to HDAC and STAT3 of compound 24 was validated by western blot analysis. The study provides new tool compounds for further exploration of STAT3-HDAC pathway inhibitor achieved with a single molecule., (© 2024 John Wiley & Sons Ltd.)

Background: Aberrant expression of histone deacetylases (HDACs) and ribonucleotide reductase (RR) enzymes are commonly observed in various cancers. Researchers are focusing on these enzymes in cancer studies with the aim of developing effective chemotherapeutic drugs for cancer treatment. Targeting both HDAC and RR simultaneously with a dual HDAC/RR inhibitor has exhibited enhanced effectiveness compared to monotherapy in cancer treatment, making it a promising strategy., Objectives: The objective of the study is to synthesize and assess the anti-cancer properties of a 1,10-phenanthroline-based hydroxamate derivative, characterizing it as a novel dual HDAC/RR inhibitor., Methods: The N 1 -hydroxy-N 8 -(1,10-phenanthrolin-5-yl)octanediamide (PA), a 1,10-phenanthroline-based hydroxamate derivative, was synthesized and structurally characterized. The compound was subjected to in vitro assessments of its anti-cancer, HDAC, and RR inhibitory activities. In silico docking and molecular dynamics simulations were further studied to explore its interactions with HDACs and RRM2., Results: The structurally confirmed PA exhibited antiproliferative activity in SiHa cells with an IC 50 of 16.43 μM. It displayed potent inhibitory activity against HDAC and RR with IC 50 values of 10.80 μM and 9.34 μM, respectively. Co-inhibition of HDAC and RR resulted in apoptosis-induced cell death in SiHa cells, mediated by the accumulation of reactive oxygen species (ROS). In silico docking studies demonstrated that PA can effectively bind to the active sites of HDAC isoforms and RRM2. Furthermore, PA demonstrated a more favorable interaction with HDAC7, displaying a docking score of -9.633 kcal/mol, as compared to the standard HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), which exhibited a docking score of -8.244 kcal/mol against HDAC7., Conclusion: The present study emphasizes the prospect of designing a potential 1,10-phenanthroline hydroxamic acid derivative as a novel dual HDAC and RR-inhibiting anti-cancer molecule., (© 2024. The Author(s).)

Latest studies confirmed that abnormal function of histone deacetylase (HDAC) plays a pivotal role in formation of tumors and is a potential therapeutic target for treating breast cancer. In this research, in-silico drug discovery approaches via quantitative structure activity relationship (QSAR) and molecular docking simulations were adapted to 43 compounds of indazole derivatives with HDAC inhibition for anticancer activity against breast cancer. The QSAR models were built from multiple linear regression (MLR), and models predictability was cross-validated by leave-one-out (LOO) method. Based on these results, compounds C32, C26 and C31 from model 3 showed superior inhibitory activity with pIC 50 of 9.30103, 9.1549 and 9.1549. We designed 10 novel compounds with molecular docking scores ranging from -7.9 to -9.3 kcal/mol. The molecular docking simulation results reveal that amino acid residues ILE1122 and PRO1123 play a significant role in bonding with 6CE6 protein. Furthermore, newly designed compounds P5, P2 and P7 with high docking scores of -9.3 kcal/mol, -8.9 kcal/mol and -8.8 kcal/mol than FDA-approved drug Raloxifene (-8.5 kcal/mol) and aid in establishment of potential drug candidate for HDAC inhibitors. The in-silico ADME functionality is used in the final phase to evaluate newly designed inhibitors as potential drug candidates. The results suggest that newly designed compounds P5, P2 and P7 can be used as a potential anti-breast cancer drug candidate., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC 50s  = 51.84-74.36 nM) being more potent than SAHA reference drug (IC 50  = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn 2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin. Materials & methods: The target compounds ( 3a-c, 4a-c and 5a-c ) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). Results: Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein. Conclusion: Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo . This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.

Dual-targeting anticancer agents 4-29 are designed by combining the structural features of purine-type microtubule-disrupting compounds and HDAC inhibitors. A library of the conjugate compounds connected by appropriate linkers was synthesized and found to possess HDACs inhibitory activity and render microtubule fragmentation by activating katanin, a microtubule-severing protein. Among various zinc-binding groups, hydroxamic acid shows the highest inhibitory activity of Class I HDACs, which was also reconfirmed by three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore prediction. The purine-hydroxamate conjugates exhibit enhanced cytotoxicity against MDA-MB231 breast cancer cells, H1975 lung cancer cells, and various clinical isolated non-small-cell lung cancer cells with different epidermal growth factor receptor (EGFR) status. Pyridyl substituents could be used to replace the C2 and N9 phenyl moieties in the purine-type scaffold, which can help to improve the solubility under physiological conditions, thus increasing cytotoxicity. In mice treated with the purine-hydroxamate conjugates, the tumor growth rate was significantly reduced without causing toxic effects. Our study demonstrates the potential of the dual-targeting purine-hydroxamate compounds for cancer monotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The study of epigenetic translational modifications had drawn great interest for the last few decades. These processes play a vital role in many diseases and cancer is one of them. Histone acetyltransferase (HAT) and histone deacetylases (HDACs) are key enzymes involved in the acetylation and deacetylation of histones and ultimately in post-translational modifications. Cancer frequently exhibits epigenetic changes, particularly disruption in the expression and activity of HDACs. It includes the capacity to regulate proliferative signalling, circumvent growth inhibitors, escape cell death, enable replicative immortality, promote angiogenesis, stimulate invasion and metastasis, prevent immunological destruction, and genomic instability. The majority of tumours develop and spread as a result of HDAC dysregulation. As a result, HDAC inhibitors (HDACis) were developed, and they today stand as a very promising therapeutic approach. One of the most well-known and efficient therapies for practically all cancer types is chemotherapy. However, the efficiency and safety of treatment are constrained by higher toxicity. The same has been observed with the synthetic HDACi. Natural products, owing to many advantages over synthetic compounds for cancer treatment have always been a choice for therapy. Hence, naturally available molecules are of particular interest for HDAC inhibition and HDAC has drawn the attention of the research fraternity due to their potential to offer a diverse array of chemical structures and bioactive compounds. This diversity opens up new avenues for exploring less toxic HDAC inhibitors to reduce side effects associated with conventional synthetic inhibitors. The review presents comprehensive details on natural product HDACi, their mechanism of action and their biological effects. Moreover, this review provides a brief discussion on the structure activity relationship of selected natural HDAC inhibitors and their analogues which can guide future research to discover selective, more potent HDACi with minimal toxicity., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cancer remains a primary cause of death globally, and effective treatments are still limited. While chemotherapy has notably enhanced survival rates, it brings about numerous side effects. Consequently, the ongoing challenge persists in developing potent anti-cancer agents with minimal toxicity. The versatile nature of the quinazoline moiety has positioned it as a pivotal component in the development of various antitumor agents, showcasing its promising role in innovative cancer therapeutics. This concise review aims to reveal the potential of quinazolines in creating anticancer medications that target histone deacetylases (HDACs)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: Validating the docking procedure and maintaining the structural water molecules at HDAC8 catalytic site., Background: Molecular docking simulations play a significant role in Computer-Aided Drug Design, contributing to the development of new molecules. To ensure the reliability of these simulations, a validation process called "self-docking or re-docking" is employed, focusing on the binding mode of a ligand co-crystallized with the protein of interest., Objective: In this study, several molecular docking studies were conducted using five X-ray structures of HDAC8-ligand complexes from the PDB., Methods: Ligands initially complexed with HDAC8 were removed and re-docked onto the free protein, revealing a poor reproduction of the expected binding mode. In response to this, we observed that most HDAC8-ligand complexes contained one to two water molecules in the catalytic site, which were crucial for maintaining the cocrystallized ligand., Results: These water molecules enhance the binding mode of the co-crystallized ligand by stabilizing the proteinligand complex through hydrogen bond interactions between ligand and water molecules. Notably, these interactions are lost if water molecules are removed, as is often done in classical docking methodologies. Considering this, molecular docking simulations were repeated, both with and without one or two conserved water molecules near Zn +2 in the catalytic cavity. Simulations indicated that replicating the native binding pose of co-crystallized ligands on free HDAC8 without these water molecules was challenging, showing greater coordinate displacements (RMSD) compared to those including conserved water molecules from crystals., Conclusion: The study highlighted the importance of conserved water molecules within the active site, as their presence significantly influenced the successful reproduction of the ligands' native binding modes. The results suggest an optimal molecular docking procedure for validating methods suitable for filtering new HDAC8 inhibitors for future experimental assays., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chrysin (5,7-dihydroxyflavone, 6) and galangin 3-methyl ether (5,7-dihydroxy-3-methoxy flavone, 7) were obtained from the leaves of Oroxylum indicum (L.) Kurz in 4% and 6% yields, respectively. Both compounds could act as pan-histone deacetylase (HDAC) inhibitors. Structural modification of these lead compounds provided thirty-eight derivatives which were further tested as HDAC inhibitors. Compounds 6b, 6c, and 6q were the most potent derivatives with the IC 50 values of 97.29 ± 0.63 μM, 91.71 ± 0.27 μM, and 96.87 ± 0.45 µM, respectively. Molecular docking study indicated the selectivity of these three compounds toward HDAC8 and the test against HDAC8 showed IC 50 values in the same micromolar range. All three compounds were further evaluated for the anti-proliferative activity against HeLa and A549 cell lines. Compound 6q exhibited the best activity against HeLa cell line with the IC 50 value of 13.91 ± 0.34 μM. Moreover, 6q was able to increase the acetylation level of histone H3. These promising HDAC inhibitors deserve investigation as chemotherapeutic agents for treating cancer., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics due to their ability to induce differentiation, cell cycle arrest, and apoptosis in cancer cells. In the present review, we have described the systemic discovery and development of HDAC inhibitors. Researchers across the globe have identified various small molecules like benzo[d][1,3]dioxol derivatives, belinostat analogs, pyrazine derivatives, quinazolin-4-one-based derivatives, 2,4-imidazolinedione derivatives, acridine hydroxamic acid derivatives, coumarin derivatives, tetrahydroisoquinoline derivatives, thiazole-5-carboxamide, salicylamide derivatives, β-peptoid-capped HDAC inhibitors, quinazoline derivatives, benzimidazole and benzothiazole derivatives, and β- elemene scaffold containing HDAC inhibitors. Most of the scaffolds have shown attractive IC50 (μM) in various cell lines like HDAC1, HDAC2, HDAC6, PI3K, HeLa, MDA-MB-231, MCF-10A, MCF-7, U937, K562 and Bcr-Abl cell lines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since coumarin and hydroxamic acid compounds are well-known in medicinal chemistry, a variety of their derivatives have been highlighted due to their potential uses for plentiful treatments. Different compounds of their derivatives acting through diverse activities, such as anti-tumor, anti-cancer, anti-inflammation, and histone deacetylase inhibition, have been comprehensively investigated by many researchers over the years. This present review provides the latest literature and knowledge on hydroxamic acids derived from coumarin. Overall, some recent advancements in biological activities of hybrid derivatives of hydroxamic acids containing coumarin moieties in medicinal chemistry are discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH 3 /NH 2 at R 2 position possess selective antiproliferative activity. However, only those with an NH 2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

Histone deacetylases (HDACs) have been identified as promising targets for anticancer treatment. The study demonstrates virtual screening, molecular docking, and synthesis of 4-(2-aminoethyl) phenol derivatives as HDAC inhibitors. The virtual screening and molecular docking analysis led to the identification of 10 representative compounds, which were evaluated based on their drug-like properties. The results demonstrated that these compounds effectively interacted with the active site pocket of HDAC 3 through π-stacking, Zn 2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues. Furthermore, a series of 4-(2-aminoethyl) phenol derivatives were synthesized, and their HDAC inhibitory activity was evaluated. Compounds 18 and 20 showed significant HDAC inhibitory activity of 64.94 ± 1.17% and 52.45 ± 1.45%, respectively, compared to the solvent control. The promising results of this study encourage further research on 4-(2-aminoethyl) phenol derivatives and may provide significant insight into the design of novel small molecule HDAC inhibitors to fight against target-specific malignancies of chronic obstructive pulmonary disease and nonsmall cell lung cancer in the future., (© 2023 Wiley Periodicals LLC.)

Histone deacetylases (HDACs) are a class of enzymes that are responsible for the removal of acetyl groups from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes, such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis, which make it an excellent target for anticancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified, with numerous HDACis being discovered, and five of them have reached the market. However, currently available HDAC always suffers from several shortcomings, such as limited efficacy, drug resistance, and toxicity. Accordingly, dual-targeting HDACis have attracted much attention from academia to industry, and great advances have been achieved in this area. In this review, we summarize the progress on inhibitors with the capacity to concurrently inhibit tubulin polymerization and HDAC activity and their application in cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Histone deacetylase 8 (HDAC8) is a zinc-dependent HDAC that catalyzes the deacetylation of nonhistone proteins. It is involved in cancer development and HDAC8 inhibitors are promising candidates as anticancer agents. However, most reported HDAC8 inhibitors contain a hydroxamic acid moiety, which often causes mutagenicity. Therefore, we used machine learning for drug screening and attempted to identify non-hydroxamic acids as HDAC8 inhibitors. In this study, we established a prediction model based on the random forest (RF) algorithm for screening HDAC8 inhibitors because it exhibited the best predictive accuracy in the training dataset, including data generated by the synthetic minority over-sampling technique (SMOTE). Using the trained RF-SMOTE model, we screened the Osaka University library for compounds and selected 50 virtual hits. However, the 50 hits in the first screening did not show HDAC8-inhibitory activity. In the second screening, using the RF-SMOTE model, which was established by retraining the dataset including 50 inactive compounds, we identified non-hydroxamic acid 12 as an HDAC8 inhibitor with an IC 50 of 842 nM. Interestingly, its IC 50 values for HDAC1 and HDAC3-inhibitory activity were 38 and 12 µM, respectively, showing that compound 12 has high HDAC8 selectivity. Using machine learning, we expanded the chemical space for HDAC8 inhibitors and identified non-hydroxamic acid 12 as a novel HDAC8 selective inhibitor.

Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure-activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.

The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione-thiosemicarbazone (TZD-TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds 2 - 4 , with IC 50 values against T98G and HepG2 cells in the low micromolar range. TZD-TSC 3 proved to be most toxic to cancer cell lines, with IC 50 values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC 50 values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound 3 induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using 3 on cancer cell lines alters these cells' morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that 3 would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD-TSC 3 represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities.

Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer's disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC 50 = 3-870 nM). Notably, it protected neuron cells from H 2 O 2 -induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N -alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC 50 values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c displayed potent antiproliferative activity against leukaemia HL-60 cells and colon cancer HCT-116 cells, with IC 50 values ranging from 0.56 μM to 4.21 μM. Molecular docking and energy scoring functions further analysed the differences in the binding modes of 11c with HDAC1/6. In vitro anticancer studies revealed that the hit compounds 11b and 11c effectively induced histone H3 acetylation, S-phase cell cycle arrest, and apoptosis in HL-60 cells in a concentration-dependent manner.

β -Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f , which exhibited potent inhibitory activity against HDACs (HDAC1: IC 50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC 50 : 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f , without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around β -elemene scaffold.

Epigenetic changes contribute to the profound alteration in the transcriptional program associated with the onset and progression of muscle wasting in several pathological conditions. Although HDACs and their inhibitors have been extensively studied in the field of muscular dystrophies, the potential of epigenetic inhibitors has only been marginally explored in other disorders associated with muscle atrophy, such as in cancer cachexia and sarcopenia. BET inhibitors represent a novel class of recently developed epigenetic drugs that display beneficial effects in a variety of diseases beyond malignancies. Based on the preliminary in vitro and preclinical data, HDACs and BET proteins contribute to the pathogenesis of cancer cachexia and sarcopenia, modulating processes related to skeletal muscle mass maintenance and/or metabolism. Thus, epigenetic drugs targeting HDACs and BET proteins may emerge as promising strategies to reverse the catabolic phenotype associated with cachexia and sarcopenia. Further preclinical studies are warranted to delve deeper into the molecular mechanisms associated with the functions of HDACs and BET proteins in muscle atrophy and to establish whether their epigenetic inhibitors represent a prospective therapeutic avenue to alleviate muscle wasting.

Histone deacetylase (HDAC) inhibitors are well-established multifaceted bioactive agents against tumors and neurodegenerative disorders. Pyrimidine and its fused and substituted derivatives were employed as a surface recognition moiety of HDAC inhibitors. De facto, the literature was loaded with different success stories of pyrimidine-based HDAC inhibitors that garnered much interest. Provoked by our continuous interest in HDAC inhibitors, we summarized and elaborated on the successful harnessing of the pyrimidine scaffold in this regard. Furthermore, we dissect our perspective that may guide medicinal chemists for an effective future design of more active chemotherapeutic agents with potential clinical applications., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

In the present study, a novel series of 11 urushiol-based hydroxamic acid histone deacetylase (HDAC) inhibitors was designed, synthesized, and biologically evaluated. Compounds 1-11 exhibited good to excellent inhibitory activities against HDAC1/2/3 (IC 50 : 42.09-240.17 nM) and HDAC8 (IC 50 : 16.11-41.15 nM) in vitro, with negligible activity against HDAC6 (>1409.59 nM). Considering HDAC8, docking experiments revealed some important features contributing to inhibitory activity. According to Western blot analysis, select compounds could notably enhance the acetylation of histone H3 and SMC3 but not-tubulin, indicating their privileged structure is appropriate for targeting class I HDACs. Furthermore, antiproliferation assays revealed that six compounds exerted greater in vitro antiproliferative activity against four human cancer cell lines (A2780, HT-29, MDA-MB-231, and HepG2, with IC 50 values ranging from 2.31-5.13 μM) than suberoylanilide hydroxamic acid; administration of these compounds induced marked apoptosis in MDA-MB-231 cells, with cell cycle arrest in the G2/M phase. Collectively, specific synthesized compounds could be further optimized and biologically explored as antitumor agents., (© 2023 Wiley-VCH GmbH.)

Tubulin and histone deacetylase have been clinically proven as promising targets for cancer therapy. Herein, we describe the design and synthesis of chiral 1,4-diarylazetidin-2-one-based hydroxamic acids as novel tubulin/HDAC dual inhibitors. Among them, compound 12a was validated to effectively disrupt tubulin polymerization, and exhibited potent HDAC1/8 inhibitory activities. Meanwhile, 12a showed good antiproliferative activities against four tumor cell lines. Further studies showed 12a works through blocking cellular cycle, inducing apoptosis and inhibiting colony formation. In addition, 12a has suitable physicochemical properties and high liver microsomal metabolic stability. Importantly, compound 12a was found to exhibit significant antitumor efficacy in vivo, thus warranting it as a promising tubulin/HDAC dual inhibitor for further development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT 1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Cancer progression is strongly affected by epigenetic events in addition to genetic modifications. One of the key elements in the epigenetic control of gene expression is histone modification through acetylation, which is regulated by the synergy between histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are thought to offer considerable potential for the development of anticancer medications, particularly when used in conjunction with other anticancer medications and/or radiotherapy. Belinostat (Beleodaq, PXD101) is a pan-HDAC unsaturated hydroxamate inhibitor with a sulfonamide group that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory or relapsed peripheral T-cell lymphoma (PTCL) and solid malignancies or and other hematological tissues. This drug modifies histones and epigenetic pathways. Because HDAC and HAT imbalance can lead to downregulation of regulatory genes, resulting in tumorigenesis. Inhibition of HDACs by belinostat indirectly promotes anti-cancer therapeutic effect by provoking acetylated histone accumulation, re-establishing normal gene expressions in cancer cells and stimulating other routes such as the immune response, p27 signaling cascades, caspase 3 activation, nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) degradation, cyclin A (G2/M phase), cyclin E1 (G1/S phase) and other events. In addition, belinostat has already been discovered to increase p21 WAF1 in a number of cell lines (melanoma, prostate, breast, lung, colon, and ovary). This cyclin-dependent kinase inhibitor actually has a role in processes that cause cell cycle arrest and apoptosis. Belinostat's clinical effectiveness, comprising Phase I and II studies within the areas of solid and hematological cancers, has been evidenced through several investigative trials that have supported its potential to be a valuable anti-cancer drug. The purpose of this research was to provide insight on the specific molecular processes through which belinostat inhibits HDAC. The ability to investigate new therapeutic options employing targeted therapy and acquire a deeper understanding of cancer cell abnormalities may result from a better understanding of these particular routes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine ( 5h ) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one ( 6l ) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC 50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.

The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor-valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673-PARP1 inhibitor-PARPi) and/or Dacarbazine (DTIC-alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies.

Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases ( 19-30 ) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC 50 values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.