CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS

2005 ◽  
Vol 45 (1) ◽  
pp. 495-528 ◽  
Author(s):  
Daryl C. Drummond ◽  
Charles O. Noble ◽  
Dmitri B. Kirpotin ◽  
Zexiong Guo ◽  
Gary K. Scott ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Clinical Activity ◽  
Innovative Drug ◽  
Nonhistone Proteins ◽  
Drug Classes

Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 546-556
Author(s):  
Duong T. Anh ◽  
Nguyen T. Thuan ◽  
Pham-The Hai ◽  
Le-Thi-Thu Huong ◽  
Nguyen T.K. Yen ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Inhibitory Potency

Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

scholarly journals Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

2012 ◽  
Vol 56 (7) ◽  
pp. 3849-3856 ◽  
Author(s):  
Subathdrage D. M. Sumanadasa ◽  
Christopher D. Goodman ◽  
Andrew J. Lucke ◽  
Tina Skinner-Adams ◽  
Ishani Sahama ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
Parasite Life Cycle ◽  
Nonhistone Proteins ◽  
Content Type

ABSTRACTHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, thein vitroandin vivoantiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth ofPlasmodium falciparumasexual-stage parasitesin vitro(50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited thein vitrogrowth of exoerythrocytic-stagePlasmodiumparasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimentalin vivomurine model of cerebral malaria, orally administered SB939 significantly inhibitedP. bergheiANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

scholarly journals Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat

2020 ◽  
Author(s):  
Tizita Z. Zeleke ◽  
Qingfei Pan ◽  
Cody Chiuzan ◽  
Maika Onishi ◽  
Mariano J. Alvarez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Hdac Inhibitors ◽  
Predictive Biomarker ◽  
Clinical Activity ◽  
Clinical Use ◽  
Breast Cancers ◽  
Study Results ◽  
Hdac6 Inhibitor

ABSTRACTDespite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients.We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ∼3,000 primary human breast cancers showed that ∼30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2-disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective, CLIA certified predictive biomarker of ricolinostat sensitivity in multiple human cancers.SIGNIFICANCEThe clinical use of HDAC inhibitors is hampered by the toxicity associated with blocking multiple HDACs. Here, we show that the specific HDAC6 inhibitor ricolinostat is safe and presents clinical activity in breast cancers and that the HDAC6 score has predictive biomarker potential to identify patients who can benefit from this therapy.

scholarly journals LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Mengxing Li ◽  
Suryavathi Viswanadhapalli ◽  
Bindu Santhamma ◽  
Uday P. Pratap ◽  
Yiliao Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Efficacy ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Hdac Inhibitors ◽  
Rna Seq ◽  
Leukemia Inhibitory Factor Receptor ◽  
Targeted Inhibition

AbstractHistone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.

Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents

2020 ◽  
Vol 27 (15) ◽  
pp. 2449-2493 ◽  
Author(s):  
Loredana Cappellacci ◽  
Diego R. Perinelli ◽  
Filippo Maggi ◽  
Mario Grifantini ◽  
Riccardo Petrelli
Keyword(s):  
Clinical Trials ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Modeling Tools ◽  
Anti Cancer

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.

Design, Synthesis and Biological Evaluation of a Novel Series of Thiadiazole-Based Anticancer Agents as Potent Angiogenesis Inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Burcugül Altuğ-Tasa ◽  
Betül Kaya-Çavuşoğlu ◽  
Ayşe T. Koparal ◽  
Gülhan Turan ◽  
Ali S. Koparal ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Biological Evaluation ◽  
Tube Formation ◽  
In Vivo Studies ◽  
Human Cancer Cell Lines ◽  
Ic50 Values

Background: Thiadiazole has attracted a great deal of interest as a versatile heterocycle for the discovery and development of potent anticancer agents. Thiadiazole derivatives exert potent antitumor activity against a variety of human cancer cell lines through various mechanisms. Objective: The goal of this work was to design and synthesize thiadiazole-based anticancer agents with anti-angiogenic activity. Methods: N-aryl-2-[(5-(aryl)amino-1,3,4-thiadiazol-2-yl)thio]acetamides (4a-r) were synthesized via the reaction of 5-(aryl)amino-1,3,4- thiadiazole-2(3H)-thiones with N-(aryl)-2-chloroacetamides in the presence of potassium carbonate. The compounds were investigated for their cytotoxic effects on three cancer (A549, HepG2, SH-SY5Y), two normal (HUVEC and 3T3-L1) cell lines using MTT and WST1 assays. In order to examine whether the compounds have anti-angiogenic effects or not, HUVEC were cultured on matrigel matrix to create a vascular-like tube formation. Results: Compounds 4d, 4m and 4n were more effective on A549 human lung adenocarcinoma cells than cisplatin. The IC50 values of compounds 4d, 4m and 4n for A549 cell line were found to be 7.82±0.4, 12.5±0.22, 10.1±0.52 µM, respectively when compared with cisplatin (IC50= 20±0.51 µM), whilst their IC50 values for HUVEC cell line were determined as 138.7±0.84, 78±0.44, 177.6±0.2 µM, respectively after 48 h treatment. The concentrations (10-20-50 µM) of compounds 4d, 4e, 4l, 4m, 4n, 4q and 4r were found to inhibit vascular like tube formation. Conclusion: According to their anticancer and anti-angiogenic effects, compounds 4d, 4m and 4n may be potential anticancer agents for further in vivo studies.

In vivo platform for translational drug development and biomarker discovery in pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4000-4000 ◽  
Author(s):  
M. Hidalgo ◽  
B. Rubio-Viqueira ◽  
C. Weekes ◽  
D. Song ◽  
P. Shah ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Anticancer Agents ◽  
Biomarker Discovery ◽  
Pancreas Cancer ◽  
Ex Vivo ◽  
Single Agent ◽  
Clinical Development ◽  
Genetic Features ◽  
Gene Status

4000 While there are many new agents entering clinical development, there is very little data to prioritize which agents should be explored in pancreas cancer. Furthermore, often there is no information on biomarkers that may predict the activity of these drugs in pancreas cancer. In this project, we have generated a cohort of 30 pancreatic cancer xenografts by implanting in nude mice tumor materials from surgical specimens. Molecular studies show that a) these tumors maintain the genetic features of the originator cancer such as KRAS, p53 and DPC4 gene status; b) tumors represent the heterogeneity of pancreatic cancer well (there is not selection of any genotype in the xenograft ) and c) features do not changed over time. We have used this platform to explore the activity of a battery with a total of 10 new anticancer agents including inhibitors of MAPK, EGFR, mTOR, src kinase, Ras oncogene, mitosis regulators, angiogenesis, heat shock protein and hedgehog pathway inhibitors using a methodology similar to a two stage phase II clinical trial. All agents are tested against 10 xenografts. Those inactive are not explored anymore. Active agents are tested against the full set of tumors. Thus far we have shown that inhibitors of mTOR and MAPK have substantial activity in this model while Ras interacting agents and EGFR targeted drugs have no single agent activity. For active agents, we have characterized the tumors for potential strategies and biormarkers that may predict activity using both a target-focus approach as well as general profiling approach. Signaling inhibitors are more active in tumors with evidence of activation of the targeted pathway. In addition, ex vivo assays indicate that the ability to inhibit the targeted pathway is associated with agent activity. This information may help to prioritize agents for clinical development in pancreatic cancer. [Table: see text]

The Novel Histone Deacetylase Inhibitor OSU-HDAC42 Has Class I and II Histone Deacetylase (HDAC) Inhibitory Activity and Represents a Novel Therapy for Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2807-2807
Author(s):  
Derek A. West ◽  
David M. Lucas ◽  
Melanie E. Davis ◽  
Michael D. De Lay ◽  
Amy J. Johnson ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Histone Deacetylase ◽  
Inhibitory Activity ◽  
Hdac Inhibitors ◽  
Clinical Development ◽  
Lymphocytic Leukemia ◽  
In Vivo Efficacy

Abstract Inhibitors of histone deacetylase (HDAC) have generated major interest for the treatment of multiple cancers including B-cell Chronic Lymphocytic Leukemia (CLL). To date, HDAC inhibitors introduced for clinical development in CLL have been associated either with suboptimal activity relative to concentrations required to mediate cytotoxicity in vitro (Valproic Acid, MS-275, SAHA), or demonstrate unacceptable acute or long-term toxicities (depsipeptide) that limit their clinical potential. Fortunately, several alternative HDAC inhibitors are in pre-clinical or early clinical development. One such agent currently undergoing pre-clinical testing by the National Cancer Institute-sponsored RAID program is OSU-HDAC42 (s-HDAC-42), a novel, orally bioavailable phenylbutyrate-derived HDAC inhibitor with both in vitro and in vivo efficacy against prostate cancer cells. We therefore tested OSU-HDAC42 against CD19-positive cells obtained from patients with CLL to determine its potential in this disease. The LC50 of OSU-HDAC42 in CLL cells was 0.46 uM at 48 hours of continuous incubation by MTT assay, which was corroborated by annexin V-FITC/propidium iodide flow cytometry. To determine the minimum amount of time that OSU-HDAC42 must be present to induce cell death, cells were incubated for various times, washed, resuspended in fresh media without drug, then assessed by MTT at a total of 48 hours incubation. The effects of OSU-HDAC42 were eliminated in CLL cells when drug was removed after 4 or 6 hours. However, there was a gradual increase in effect over time, and by 16 hours, approximately 60% of the cytotoxicity achieved with continuous incubation was retained. OSU-HDAC42 induced acetylation of histone proteins H3 and H4 as early as 4 hours that was dose and time dependent. LC/MS interrogation of OSU-HDAC42-treated CLL cells is currently underway to determine specific post-translational modification changes of all histone proteins and variants. OSU-HDAC42 also was able to sensitize CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL) at 24 hours in a dose-dependent manner, supporting its class I HDAC inhibitory activity as recently reported by Inoue and colleagues (Cancer Res.2006; 66:6785). Evidence of class II HDAC inhibitory activity was also observed with OSU-HDAC42 at 12 hours with acetylation of tubulin. Unlike depsipeptide, OSU-HDAC42 activated both caspase-8 and -9 followed by PARP processing. Cell death induced by OSU-HDAC42 was completely inhibited with pre-treatment by the pan-caspase inhibitor Z-VAD-FMK. In vivo experiments are underway to examine the efficacy of OSU-HDAC42 in several murine models of leukemia to confirm in vivo efficacy as well as influence on murine effector cells. Our data strongly support continued investigation of OSU-HDAC42 in CLL and related B-cell malignancies.

ACY-1215, a First-In-Class Selective Inhibitor Of HDAC6, Demonstrates Significant Synergy With Immunomodulatory Drugs (IMiDs) In Preclinical Models Of Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1952-1952 ◽  
Author(s):  
Steven N Quayle ◽  
Simon S Jones
Keyword(s):  
Selective Inhibitor ◽  
Clinical Development ◽  
Clinical Activity ◽  
Preclinical Models ◽  
Employment Equity ◽  
Phase Ib ◽  
Equity Ownership ◽  
Ongoing Phase

Abstract Histone deacetylase (HDAC) enzymes represent attractive therapeutic targets in multiple myeloma, but unfortunately non-selective HDAC inhibitors have led to dose-limiting toxicities in patients. ACY-1215 is a first generation, orally available HDAC inhibitor that is 11-fold selective for HDAC6, and synergizes in vitro and in vivo with bortezomib in preclinical models of MM without inducing unfavorable toxicities (Blood, 20[210]: 4061). Ongoing Phase Ib clinical trials with ACY-1215 have thus far confirmed an exceptional safety and tolerability profile (Raje, et al, EHA, 2013). The IMiD class of drugs, including lenalidomide and pomalidomide, exhibit striking anti-myeloma properties in a variety of MM models, and have demonstrated significant clinical activity in MM patients. Prior studies have shown clinical activity of a combination of the non-selective HDAC inhibitor vorinostat with lenalidomide and dexamethasone in myeloma patients (Richter, et al, ASH, 2011). However, many patients experienced significant toxicities with this regimen that significantly limits its clinical utility. In support of our ongoing clinical development program for ACY-1215 in MM, we show here that combining ACY-1215 with either lenalidomide or pomalidomide leads to synergistic decreases in the viability of MM cells in vitro. The relevance of inhibition of HDAC6 to this synergistic effect was validated by demonstrating synergistic interactions of either IMiD molecule with ACY-775, which is more than 300-fold selective for HDAC6 over class I HDAC’s. Further, the combination of ACY-1215, lenalidomide, and dexamethasone was well tolerated in vivo with no overt evidence of toxicity, and combination efficacy studies with this combination are now ongoing in models of MM. By demonstrating that a selective inhibitor of HDAC6 synergizes with IMiD’s while maintaining an improved safety profile, these results provided a rational basis for the clinical development of the orally available combination of ACY-1215 and lenalidomide plus dexamethasone in an ongoing Phase Ib clinical trial (NCT01583283) for the treatment of MM. Disclosures: Quayle: Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership.

scholarly journals Improved development of mouse SCNT embryos by chlamydocin analogues, class I and IIa histone deacetylase inhibitors†

2021 ◽  
Author(s):  
Satoshi Kamimura ◽  
Kimiko Inoue ◽  
Eiji Mizutani ◽  
Jin-Moon Kim ◽  
Hiroki Inoue ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Cell Stage ◽  
Inhibitory Spectrum ◽  
Developmental Block

Abstract In mammalian cloning by somatic cell nuclear transfer (SCNT), treatment of reconstructed embryos with histone deacetylase (HDAC) inhibitors improves efficiency. So far, most of those used for SCNT are hydroxamic acid derivatives—such as trichostatin A—characterized by their broad inhibitory spectrum. Here, we examined whether mouse SCNT efficiency could be improved using chlamydocin analogues, a family of newly designed agents that specifically inhibit Class I and IIa HDACs. Development of SCNT-derived embryos in vitro and in vivo revealed that four out of five chlamydocin analogues tested could promote the development of cloned embryos. The highest pup rates (7.1 to 7.2%) were obtained with Ky-9, similar to those achieved with trichostatin A (7.2 to 7.3%). Thus, inhibition of Class I and/or IIa HDACs in SCNT-derived embryos is enough for significant improvements in full-term development. In mouse SCNT, the exposure of reconstructed oocytes to HDAC inhibitors is limited to 8–10 h because longer inhibition with Class I inhibitors causes a 2-cell developmental block. Therefore, we used Ky-29, with higher selectivity for Class IIa than Class I HDACs for longer treatment of SCNT-derived embryos. As expected, 24-h treatment with Ky-29 up to the 2-cell stage did not induce a developmental block, but the pup rate was not improved. This suggests that the 1-cell stage is a critical period for improving SCNT cloning using HDAC inhibitors. Thus, chlamydocin analogues appear promising for understanding and improving the epigenetic status of mammalian SCNT-derived embryos through their specific inhibitory effects on HDACs.

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