Class Of Histone Deacetylase Inhibitors Research Articles

Chidamide As Maintenance in Peripheral T-Cell Lymphoma for Patients in Response after Induction Therapy: A Single Center Retrospective Study

Background Peripheral T-cell lymphoma (PTCL) is a set of heterogeneous mature T- and natural killer cell neoplasms, most of which are associated with poor prognosis. PTCL patients usually experience frequent relapses. To improve the poor clinical outcomes of PTCL, novel agents that target various pathways have been studied and developed. Histone deacetylase (HDAC) inhibitors are among the most significant improvements made in recent years. Chidamide, a novel benzamide class of HDAC inhibitor, showed significant efficacy in relapsed/refractory PTCL patients in previous studies. But the role chidamide of as a maintenance therapy in PTCL patients after first-line therapy is still unknown. Methods In this retrospective, single-center, single-arm study, a total of 342 newly diagnosed PTCL patients were reviewed in the First Affiliated Hospital, Zhejiang University School of Medicine (Zhejiang, China) from August 2014 to May 2022. Patients with natural killer/T-cell lymphoma, mycosis fungoides were not enrolled. After excluding patients with insufficient clinical data, with other concurrent tumor, received other anti-tumor agents during maintenance therapy, or underwent sequential transplantation, there were 35 PTCL patients achieved objective response after first-line therapy, and received chidamide as maintenance therapy. The primary endpoint of this study was progress-free survival (PFS), overall survival (OS), and adverse events (AEs). Response and progression data were evaluated according to the 2016 Lugano Classification lymphoma response criteria. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 4.0. Survival outcomes were assessed with Kaplan-Meier method. Results 35 PTCL patients were enrolled, including angioimmunoblastic T-cell lymphoma (AITL) (13, 37.1%), anaplastic large-cell lymphoma (ALCL) (2, 5.7%), PTCL-NOS (20, 57.1%). There were 22 (62.9%) males and 13 (37.1%) females, 16 (45.7%) patients were over 65 years old, 32 patients (91.4%) had clinical stage III-IV, 9 patients (25.7%) had B symptoms, 8 patients (22.9%) had ECOG score ≥2, 15 patients (42.9%) with IPI score ≥3-5, 18 (51.4%) achieved complete remission (CR) and 17 (48.6%) achieved partial remission (PR) after induction chemotherapy. The median follow-up time was 35.2 months (range 13.0 to 107.7). The median duration of chidamide maintenance therapy was 17.7 months (range 2.4 to 98.0). 22 (62.9%) patients received 20mg chidamide twice a week and 13 (37.1%) used 30mg twice a week . The median PFS and median OS were not reached. The 3-year PFS and OS were 64.9% and 89.2%. Patients who achieved CR after induction chemotherapy had a better prognosis trend. Among the 18 patients who received maintenance therapy after CR, there was no death and the 3-year PFS was 76.4%. Patients with B symptoms had a worse prognosis (P<0.05), the median PFS was 22.5 months, the median OS was not reached, and the 3-year overall survival rate was 75%. The 3-year PFS and OS of the remaining 26 patients without B symptoms were 78.5% and 94.1%, respectively. The most common grade 3-4 AEs were hematological toxicities, including neutropenia(20.0%), anemia(8.6%), thrombocytopenia(5.7%), mainly in 30mg group, as detailed in Table 1. Adverse events usually occurred during the first 6 weeks, most of with were manageable by supportive care and dose modification, none of the adverse reactions leaded to death. There was no statistical difference in PFS and OS between the 30mg and 20mg groups under current sample size. Conclusions Chidamide maintenance is effective and may prolong the PFS and OS for PTCL patients with manageable safety profile. It is an appropriate therapeutic option as up-front consolidation therapy for PTCL patients with complete or partial response after first-line therapy. Larger-sample, prospective, multicenter cohort study is still needed to further confirm the conclusion.

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity.

Inhibitors of histone deacetylases (HDACs) have received special attention as novel anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the N-(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the amino acids pyroglutamic acid and proline. We have identified benzamides that inhibit HADC1 and HDAC2 at nanomolar concentrations, with antiproliferative activity at micromolar concentrations against A549 and SF268 cancer cell lines. Docking studies shed light on the mode of binding of benzamide inhibitors to HDAC1, whereas cellular analysis revealed downregulated expression of EGFR mRNA and protein. Two benzamides were investigated in a mouse model of bleomycin-induced pulmonary fibrosis, and both showed efficacy on a preventative dosing schedule. N-(2-Aminophenyl)-benzamide inhibitors of class I HDACs might lead to new approaches for treating fibrotic disorders.

Rational design of metabolically stable HDAC inhibitors: An overhaul of trifluoromethyl ketones

Epigenetic regulation of gene expression using histone deacetylase (HDAC) inhibitors is a promising strategy for developing new anticancer agents. The most common HDAC inhibitors are hydroxamates, which, though highly potent, have limitations due to their poor pharmacokinetic properties and lack of isoform selectivity. Trifluoromethylketones (TFMK) developed as alternatives to hydroxamates are rapidly metabolized to inactive trifluoromethyl alcohols in vivo, which prevented their further development as potential drug candidates. In order to overcome this limitation, we designed trifluoropyruvamides (TFPAs) as TFMK surrogates. The presence of an additional electron withdrawing group next to the ketone carbonyl group made the hydrate form of the ketone more stable, thus preventing its metabolic reduction to alcohol in vivo. In addition, this structural modification reduces the potential of the TFMK group to act as a covalent warhead to eliminate off-target effects. Additional structural changes in the cap group of the inhibitors gave analogues with IC50 values ranging from upper nanomolar to low micromolar in the cytotoxicity assay, and they were more selective for cancer cells over normal cells. Some of the most active analogues inhibited HDAC enzymes with low nanomolar IC50 values and were found to be more selective for HDAC8 over other isoforms. These molecules provide a new class of HDAC inhibitors with a metabolically stable metal-binding group that could be used to develop selective HDAC inhibitors by further structural modification.

Abstract 5474: A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling

Abstract Background: Mounting epidemiological and experimental evidences strongly suggest that epigenetic processes including histone modifications are involved in the development of drug resistance in breast cancer. Histone deacetylases (HDACs) selective inhibition is an important strategy of anticancer drug discovery field. However, lack of HDACs isozymes selective inhibitors associated with adverse side effects that limits their clinical applications. We have recently reported new and selective HDACs inhibitors displaying varying HDAC isozyme selectivity degrees that resulted in increased histones acetylation and apoptosis induction in cancer cells. In the present study, we investigated molecular mechanisms underlying anticancer potential of these molecules in breast cancer cells. Experimental methods: Proliferation ability, invasion capacity, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) major group’s gene expressions and protein levels, and the gelatinolytic activity of MMPs were analyzed after treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with HDACs inhibitors compounds. Results and Discussions: Two compounds, identified as MAL-4 and MAL-5, were selected based on the half-maximal inhibitory concentration (IC50) in both breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cells with 5 µM MAL-4 and MAL-5 significantly induces TIMP-2 mRNA and protein levels whereas MMP-2 and MMP-9 content and activities were reduced. Further analyses showed that MAL-4 and MAL-5 attenuated invasion capability of breast cancer cells. Conclusion: We have demonstrated that the new compounds can be used as potential lead drug candidates for an effective anti-metastatic therapy mediated by HDAC inhibition in breast cancer. Citation Format: Khuloud Bajbouj, Lina Sahnoon, Abeer AL-Ali, Jasmin Shafarin, Leonie Binder, Reem Abdul Rehman, Rafat El-Awady, Taleb H. Al-Tel. A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5474.

Cysteine derivatives as acetyl lysine mimics to inhibit zinc-dependent histone deacetylases for treating cancer.

Zinc-dependent histone deacetylases (HDACs) are important epigenetic regulators that have become important drug targets for treating cancer. Although five HDAC inhibitors have been approved for treating several cancers, there is still a huge demand on discovering new HDAC inhibitors to explore the therapeutic potentials for treating solid tumor cancers. Substrate mimics are a powerful rational design approach for the development of potent inhibitors. Here we describe the rational design, synthesis, biological evaluation, molecular docking and invivo efficacy study of a class of HDAC inhibitors using Nε-acetyl lysine mimics that are derived from cysteine. As a result, compounds 7a, 9b and 13d demonstrated pan-HDAC inhibition and broad cytotoxicity against several cancer cell lines, comparable to the approved HDAC inhibitor SAHA. Furthermore, 13d significantly inhibited tumor growth in a A549 xenograft mice model without any obvious weight loss, supporting that the cysteine-derived acetyl lysine mimics are promising HDAC inhibitors with therapeutic potentials for treating cancer.

Chidamide Maintenance Therapy after Induction or Salvage Treatment in Patients with Peripheral T-Cell Lymphoma Ineligible for Autologous Stem Cell Transplantation

BackgroundPeripheral T-cell lymphoma (PTCL) is a set of rare and heterogeneous clinically aggressive mature T- and natural killer cell neoplasms, all of which are associated with poor prognosis. PTCL treatments are usually associated with a high failure rate and frequent relapses. To improve the poor clinical outcomes of PTCL, novel agents that target various pathways have been intensively studied and developed. Histone deacetylase (HDAC) inhibitors are among the most significant improvements made in recent years. Chidamide, a novel benzamide class of HDAC inhibitor, showed significant efficacy in relapsed/refractory PTCL patients in previous studies. In China, a high percentage of PTCL patients are elderly and not suitable for transplantation, and many patients cannot afford transplantation. There is an urgent medical need for maintenance therapy for PTCL patients, and chidamide single-agent maintenance therapy may benefit PTCL patients ineligible for autologous stem cell transplantation (ASCT) with its proven outstanding antitumor effects.MethodsIn this prospective, single-center, single-arm study, a total of 43 patients with PTCL, including angioimmunoblastic T-cell lymphoma (AITL) (44.2%), anaplastic large-cell lymphoma, ALK − (ALCL, ALK −) (11.6%), PTCL-not otherwise specified (PTCL-NOS) (14.0%), extranodal NK/T-cell lymphoma (NKT) (16.3%), and other PTCL subtypes (14.0%), were enrolled from January 2016 to March of 2021. All patients were ineligible for transplantation. They had a median age of 59 years (22-80). Thirty-six patients (83.7%) received chidamide maintenance after induction treatment, and 7 patients (16.3%) started chidamide maintenance treatment after salvage treatment. Endpoints included progress-free survival (PFS), overall survival (OS), and safety assessment.ResultsUntil April 2021, the median follow-up time was 10.1 months (2-64.5). The complete remission rate (CR) was 44.2% and overall response rate (ORR) was 79.1%. The median PFS was 24.3 m, and the 1-year PFS rate was 68.1%. The median OS has not yet been reached, and 1-year OS rate was 84.3%. Stratified analyses of PFS and OS showed no significant differences. Grade 3/4 adverse events were mainly hematological toxicities, including neutropenia, leukopenia, thrombocytopenia, and anemia, and they were well tolerated.When used a first-line/1.5-line treatment, i.e., for patients who had achieved CR after introduction treatment (12 cases) or who did not achieve CR but received chidamide + chemotherapy consolidation treatment (24 cases), chidamide maintenance therapy was found to maintain the effect of CR (in all 12 patients) or improve the clinical outcomes to CR/PR (partial remission) (9 out of the 24 patients). Even when used after salvage treatment, chidamide maintenance was found to achieve PR and better efficacy in 4 out the 7 patients.ConclusionsChidamide maintenance treatment achieved significantly high CR and ORR rates for PTCL patients. This therapy may improve PFS and OS with a manageable safety profile for PTCL patients. This treatment thus may benefit PTCL patients who are ineligible for or cannot afford ASCT, which is an especially severe problem in China. Further large-scale, multi-center, randomized studies are required to extensively examine the efficacy and safety of chidamide maintenance therapy in PTCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chidamide ,Oral Subtype-Selective Histone Deacetylase Inhibitor (HDACI) Monotherapy Was Effective on the Patients with Relapsed or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma

Background:Chidamide is an orally bioavailable benzamide class of histone deacetylase inhibitor (HDACi), that selectively inhibits activity of HDAC1, 2, 3 and 10. It was approved by the Chinese FDA for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). However, the efficacy and safety of Chidamide remain to be determined in relapsed or refractory extranodal natural killer T-cell lymphoma (ENKTCL), and the optimal dosing schedule was unclear. The purpose of the current study were to evaluate the clinical response and toxicity for R/R-ENKTCL at two dosing schedule of Chidamide monotherapy.Methods:This is an open-label, prospective phase II trial in China. Inclusion criteria included histologically confirmed ENKTCL, disease progression or non-response after asparaginase-based chemotherapy. Chidamide 30mg BIW or 10mg daily was taken at least 6 weeks until disease progression or the occurrence of unacceptable toxicity. Utility of PET-CT in the therapeutic evaluation was employed. Serum EBV-DNA was monitored weekly. At the time of this abstract submission, the trial is still ongoing.Results: A total of 15 relapsed or refractory ENKTCL patients failed to asparaginase-based chemotherapy or autologous hematopoietic stem cell transplantation (ASCT) were enrolled in this study (10mg QD group, n=9 and 30mg BIW group, n=6, respectively). Median previous chemotherapy regimens was 3(2-5), 2 patient relapsed following ASCT. 12 patients were evaluable for response and 3 patients still under treatment less than 6 weeks. ORR was 50.0% (6/12) with CR rate 33.3 %(4/12) . Three patients got CR in 30mg group, one patient got CR in 10mg group (table1,figure 1). The median time to response was 5.9 (1.1 to 8.1) weeks. Median follow-up time was 3.7 months (0.8-11.5) so far. All four CR patients were still in disease-free more than 6.9 months (6.9-10.5). Serum EBV-DNA load during the course of treatment was declined or stable in all responders only two cases with elevated EBV-DNA level observed due to disease progression (figure 2). Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 hematologic toxicity were similar in both groups included neutropenia (50.0% vs. 44.4%) and thrombocytopenia (33.3% vs. 33.3%). 30mg group experienced a higher incidence of nausea and vomiting(100% vs. 44.4%). Meanwhile, we also treated six refractory B cell lymphoma patients, including three diffused large B cell lymphoma (DLBCL), two mantle cell lymphoma (MCL) and one follicular lymphoma. One DLBCL patient and one MCL patient obtained PR respectively.Conclusions: Our study suggested that Chidamide was effective as single agent in the treatment of relapsed or refractory malignant lymphoma.. The therapeutic outcome for previous heavily-treated ENKTCL was encouraged without clinical EBV reactivation. It is too early to draw conclusions of response difference between two dosing schedule. Further clinical trial warranted.(ClinicalTrials.gov, NCT 2878278 )Disclosures: No relevant conflicts of interest to declare. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Discovery of novel class of histone deacetylase inhibitors as potential anticancer agents

Selective inhibition of histone deacetylases (HDACs) is an important strategy in the field of anticancer drug discovery. However, lack of inhibitors that possess high selectivity toward certain HDACs isozymes is associated with adverse side effects that limits their clinical applications. We have initiated a collaborative initiatives between multi-institutions aimed at the discovery of novel and selective HDACs inhibitors. To this end, a phenotypic screening of an in-house pilot library of about 70 small molecules against various HDAC isozymes led to the discovery of five compounds that displayed varying degrees of HDAC isozyme selectivity. The anticancer activities of these molecules were validated using various biological assays including transcriptomic studies. Compounds 15, 14, and 19 possessed selective inhibitory activity against HDAC5, while 28 displayed selective inhibition of HDAC1 and HDAC2. Compound 22 was found to be a selective inhibitor for HDAC3 and HDAC9. Importantly, we discovered a none-hydroxamate based HDAC inhibitor, compound 28, representing a distinct chemical probe of HDAC inhibitors. It contains a trifluoromethyloxadiazolyl moiety (TFMO) as a non-chelating metal-binding group. The new compounds showed potent anti-proliferative activity when tested against MCF7 breast cancer cell line, as well as increased acetylation of histones and induce cells apoptosis. The new compounds apoptotic effects were validated through the upregulation of proapoptotic proteins caspases3 and 7 and downregulation of the antiapoptotic biomarkers C-MYC, BCL2, BCL3 and NFĸB genes. Furthermore, the new compounds arrested cell cycle at different phases, which was confirmed through downregulation of the CDK1, 2, 4, 6, E2F1 and RB1 proteins. Taken together, our findings provide the foundation for the development of new chemical probes as potential lead drug candidates for the treatment of cancer.

Design, Synthesis and Biological Activity of New Hydroxamic Acids Containing 2-Imidazolylphenyl(oxy/thio)alkanoic Fragment

Background: Histone Deacetylase (HDAC) inhibitors are a new class of therapeutic compounds that show promising results in a series of preclinical and clinical anticancer studies. Hydroxamic acids belong to one of the most significant classes of HDAC inhibitors. The member vorinostat (SAHA) was approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. Methods: A series of eight novel hydroxamic acids containing 2-imidazolylphenyl(oxy/thio) alkanoic fragment designed to target Histone Deacetylase (HDAC) were synthesized in five steps from easily accessible 2(3H)-benzoxazolones and 2(3H)-benzthiazolones. The newly synthesized compounds were characterized by 1H, 13C NMR, and elemental analysis. Results: The structure-activity relationship was examined via linker length alternation and variation of the heteroatom (oxygen or sulfur) and chlorine substitution pattern of the starting materials. The compounds were tested for their cytotoxic activity against two human cancer cell lines (HT-29 and MDA-MB-231). Our data indicate that the compound 6.1d is active in the micromolar range with IC50 of 9.7 μM for MDA-MB-231 cells. DNA fragmentation analysis of the most active compounds confirmed that apoptosis could be one of the mechanisms involved in cell death. Conclusion: Taken together, the results revealed that 6d may become a promising lead compound for new anticancer drugs discovery.

Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

Fluorescent Nanohybrids from ZnS/CdSe Quantum Dots Functionalized with Triantennary, N-Hydroxy-p-(4-arylbutanamido)benzamide/Gallamide Dendrons That Act as Inhibitors of Histone Deacetylase for Lung Cancer.

N-Hydroxy-p-(4-arylbutanamido)benzamides (HABAB) belong to one class of histone deacetylase inhibitors (HDACi), which regulate deacetylation of lysine residue's amino group in histone, which results in chromatin constriction. In addition, transcriptional knockdown of the genetic loci possessing the suppressor genes of tumor occurs. A tripodal, HABAB-capped gallamide dendron possessing thiol anchoring unit was prepared by the click method. The resultant hydrophilic dendritic unit was easily attached on the outer layer of CdSe/ZnS (i.e., core/shell type) quantum dots by thiolate-Zn interaction, as supported via 1H NMR spectroscopic analysis of the conjugate with its original property of fluorescence. The resulting, water-miscible nanohybrid (nano-HTPB) which bore trivalent, peripheral HABABs as the HDACi was efficiently taken up by cells of lung cancer and transported into the nuclei of cells in 3 h, as confirmed by confocal microscopy analysis. The concentration levels of 50% inhibition (IC50) after 48 h incubation of the nano-HTPB for A549 and H1299 lung cancer cell lines were 14 and 18 nM, respectively, which were about 150-fold lower than those of the parent HTPB analogues. Nano-HTPB at 20 nM induced the knockdown of cell cycle at second growth/mitosis (i.e., G2/M) transition, which eventually led to apoptosis of lung cancer cells, demonstrating that the nano-HTPB was much more potent in inhibiting lung cancer cell growth in a synergistic manner than the parent HTPB analogues. In addition, the dendritic HABAB-capped nanohybrid, nano-HTPB, is more effective than the parent HTPB analogues both in vitro and in vivo. Furthermore, the nano-HTPB is more effective than the parent HTPB to increase the acetylation level of proteins related to histone and nonhistone like p53 and tubulin. Our results confirmed that covalent encapsulation of quantum dots with peripheral, triantennary HDACis represented a feasible strategy for synergistic drug delivery with enhanced biological effects.

Synergistic Antitumor Effect and Mechanism of Chidamide Combined with Gemcitabine, Oxaliplatin or Zanubrutinib in Diffuse Large B-Cell Lymphoma

Aims: To observe the synergistic antitumor effect of chidamide (a novel orally benzamide class of histone deacetylase inhibitors, HDACi) combined with gemcitabine, oxaliplatin or zanubrutinib (a second generation Bruton's tyrosine kinase (BTK) inhibitor) in diffuse large B-cell lymphoma cell lines and explore the possible mechanisms. Methods: We used CCK-8 assay to test the inhibitory efficacy of single agent chidamide, gemcitabine, oxaliplatin, zanubrutinib and their combinations on DLBCL cell lines, respectively. And the combination index (CI) was calculated by the CalcuSyn software. The apoptosis and the cell cycle analysis of DLBCL cell lines under different treatments were assessed by Annexin V-APC/PI double-staining and PI staining using flow cytometry, respectively. The expression levels of acetylated histone and apoptosis-related proteins were detected by Western Blot. Results:Single-agent chidamide, gemcitabine and oxaliplatin caused growth arrest of the DLBCL cell lines (OCL-LY3、OCL-LY19、U2932、DOHH2) in a dose and time dependent manner, respectively(Figure1a,1b,1c). Single-agent zanubrutinib showed antitumor activity in two activated B-cell like DLBCL (U2932 and OCI-LY3) cell lines in a dose and time dependent manner while no antitumor activity in other two GCB-DLBCL (OCI-LY19 and DOHH2) cell lines (Figure1d). Chidamide combined with gemcitabine or oxaliplatin synergistically inhibited the proliferative viability of DLBCL cell lines. Also, chidamide could enhance the inhibitory effect of zanubrutinib in the two ABC-DLBCL cell lines. And the CI values of all groups were more than 1(Fig2-1~2-8). Chidamide could significantly increase the proportion of DLBCL cells in the G0/G1 phase in a dose-dependent manner(Figure 3). And chidamide combined with gemcitabine can synergistically enhance the cell cycle arrest in U2932 cells (Figure 4). Cell apoptosis rate increased along with the ascending dosage of chidamide in the four DLBCL cell lines. The effect of cell apoptosis became more obviously when combined with oxaliplatin or zanubrutinib (Figure 5.1~5.4). Chidamide significantly up-regulated the levels of acetylated H3 (Lys 9) and cleaved-caspase 3 while down-regulated Bcl-2 (Figure 6~7). Furthermore, PD-L1 protein was upregulated in chidamide-exposed DLBCL cell lines (Figure 8). Conclusion:Chidamide combined with gemcitabine, oxaliplatin or zanubrutinib synergistically inhibited the proliferative viability and cell apoptosis rate in DLBCL cell lines. Therefore, it is worthy to further explore the value of Chidamide combination therapy in DLBCL. Figure Disclosures No relevant conflicts of interest to declare.

Histone Deacetylases and Histone Deacetylase Inhibitors in Neuroblastoma.

Histone deacetylases (HDACs) are enzymes that play a key role in regulating gene expression by remodeling chromatin structure. An imbalance of histone acetylation caused by deregulated HDAC expression and activity is known to promote tumor progression in a number of tumor types, including neuroblastoma, the most common solid tumor in children. Consequently, the inhibition of HDACs has emerged as a potential strategy to reverse these aberrant epigenetic changes, and several classes of HDAC inhibitors (HDACi) have been shown to inhibit tumor proliferation, or induce differentiation, apoptosis and cell cycle arrest in neuroblastoma. Further, the combined use of HDACi with other chemotherapy agents, or radiotherapy, has shown promising pre-clinical results and various HDACi have progressed to different stages in clinical trials. Despite this, the effects of HDACi are multifaceted and more work needs to be done to unravel their specific mechanisms of actions. In this review, we discuss the functional role of HDACs in neuroblastoma and the potential of HDACi to be optimized for development and use in the clinic for treatment of patients with neuroblastoma.

Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents.

Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

Bioinformatics analysis of the network of histone H3 lysine 9 trimethylation in acute myeloid leukaemia.

Changes in histone H3 lysine 9 trimethylation (H3K9me3) may be related to the development of drug-resistant acute myeloid leukaemia (AML); insights into the network of H3K9me3 may improve patient prognosis. Patient data were derived from the Gene Expression Omnibus (GEO) database and data from AML cells treated with chidamide, a novel benzamide chemical class of histone deacetylase inhibitor (HDACi), in vitro were derived from ChIP-seq. Patients and AML cell data were analysed using GEO2R, GOseq, KOBAS, the STRING database and Cytoscape 3.5.1. We identified several genes related to the upregulation or downregulation of H3K9me3 in AML patients; some of these genes were related to apoptosis, autophagy, and the pathway of cell longevity. AML cells treated with chidamide in vitro showed the same gene changes. The protein interactions in the network did not have significantly more interactions than expected, suggesting the need for more research to identify these interactions. One compelling result from the protein interaction study was that sirtuin 1 (SIRT1) may have an indirect interaction with lysine-specific demethylase 4A (KDM4A). These results help explain alterations of H3K9me3 in AML that may direct further studies aimed at improving patient prognosis. These results may also provide a basis for chidamide as a treatment strategy for AML patients in the future.

Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA-MB-468 (IC50 = 0.65 μM), and liver cancer cells HepG2 (IC50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents.

Design and synthesis of imidazole based zinc binding groups as novel small molecule inhibitors targeting Histone deacetylase enzymes in lung cancer

Histone deacetylase enzymes are involved in the remodelling of chromatin and have a pivotal role in balancing acetylation and deacetylation status of chromatin eventually ensures the epigenetic regulation of gene expression. Its aberrant activity was reported in several forms of cancer considering it as a potential target for cancer treatment. Histone deacetylase inhibitors emerged as new class of antineoplastic drugs. Recent developments in understanding the mechanism of interaction between drug and targeted molecule encourages rational development of new class of HDAC inhibitors directing global or gene specific histone acetylation. In the present study, we designed 14 imidazole based derivatives abiding the common pharmacophore structure like CAP, Spacer, and Zinc binding group (ZBG) shared among the established HDAC inhibitors and was explored for its epigenetic modulator candidature targeting histone modifying enzymes through docking experiments. Among them the compound ethyl (2,5-diphenyl-1H-imidazole-4-yl)acetate (C3) was tightly bound to the isoforms of the HDAC enzymes at their receptor regions with high binding score. C3 was synthesized and have been characterized experimentally by IR and NMR techniques. The C3 inhibit cell proliferation of A549 lung cancer cell by inducing cytotoxicity and increased levels of ROS generation by disrupting mitochondrial permeability as evidenced from deflection in (Δψm). From this study we revealed that C3 a novel imidazole derivative inhibit highly expressed HDAC enzyme in non-small cell lung cancer cell lines by chromatin remodelling. Further findings may validate the identified compound C3 as an effective epigenetic modulator.

Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update.

Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.

Targeting miRNAs by histone deacetylase inhibitors (HDACi): Rationalizing epigenetics-based therapies for breast cancer.

MicroRNAs (miRNAs) belong to a group of short RNA molecules of ~22 nucleotides that play a significant role in the regulation of gene expression through post-transcriptional regulatory mechanisms. They can directly interact with their target mRNA molecules and induce target gene silencing. Many investigations over the past decade have revealed the involvement of different miRNAs in essential biological events. The expression of a considerable number of miRNAs is tightly regulated through epigenetic events such as histone modifications and DNA methylation. Notably, irregularities in these epigenetic events are associated with aberrant expression of miRNAs in a range of diseases including cancer. Impaired epigenetic events associated with aberrant expression of miRNAs can be pharmacologically modified using chromatin modifying drugs. Numerous pre-clinical and clinical data demonstrate that histone deacetylase inhibitors (HDACi) can re-establish the expression of aberrantly expressed miRNAs in a range of cancer types, rationalizing miRNAs as potential drug targets. This review highlights evidence from investigations assessing the effects of different classes of HDACi on miRNA expression in breast cancer (BC).

Abstract 4718: SR-4370, a potent and selective inhibitor of class I HDACs, suppresses AR signaling and in vivo prostate tumor growth

Abstract Androgen receptor (AR) is an androgen-activated transcription factor and drives prostate cancer (PCa) progression. Class I HDACs 1-3 are critical for activating AR-mediated transcription. Thus, targeting these HDACs is a promising strategy for treating PCa. Notably, along with significant adverse effects, several FDA-approved HDAC inhibitors broadly inhibiting different HDACs were ineffective for treating castration-resistant prostate cancer in clinical trials. Significantly, entinostat, an aminobenzamide analog specific to HDACs 1-3, extended overall survival for patients with breast cancer resistant to endocrine therapy. These observations suggest that HDACi selective to HDACs 1-3 may be effective for treating solid tumors including PCa. We have recently discovered the novel benzoylhydrazide class of HDAC inhibitors highly specific to HDACs 1-3. An optimized analog, SR-4370, exhibited low µM to nM potency against HDACs 1-3. SR-4370 markedly suppressed AR signaling, PCa cell proliferation in vitro, and prostate tumor growth in vivo. Gene expression profiling experiments revealed that SR-4370 downregulated AR, AR-Vs and AR target genes as well as the MYC oncogenic network. Chromatin accessibility assay using ATAC-seq showed that SR-4370 altered chromatin states in PCa cells. The chromatins with AR-binding sites became inaccessible on SR-4730 treatment, indicating that altered chromatin accessibility may contribute to the inhibition of AR signaling. Interestingly, SR-4370 sensitized C4-2 cells to enzalutamide. In PCa xenograft models, SR-4370 was effective to suppress tumor growth in vivo. Importantly, SR-4370 was well tolerated and did not cause observable adverse effects as judged by body weight and blood chemistry tests of treated mice. Our data suggest that SR-4370 may be a safe and clinically applicable treatment for advanced PCa refractory to current frontline treatments. (Supported by UFHealth Cancer Center, Florida Breast Cancer Foundation, James and Esther King Biomedical Research Program, and Bankhead-Coley Cancer Research Program, Florida Department of Health) Citation Format: Iqbal Mahmud, Guimei Tian, Jia Wang, Ryan Stowe, Zhiguang Huo, Yushan Zhang, Hamsa Thayek Purayil, Eric Helm, Theodore Drashansky, Dorina Avram, Yehia Daaka, William R. Roush, Daiqing Liao. SR-4370, a potent and selective inhibitor of class I HDACs, suppresses AR signaling and in vivo prostate tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4718.