HDAC inhibitor

Quinolone is a heterocyclic compound containing carbonyl at the C-2 or C-4 positions with nitrogen at the C-1 position. The scaffold was first identified for its antibacterial properties, and the derivatives were known to possess many pharmacological activities, including anticancer. In this review, the quinolin-2(H)-one and quinolin-4(H)-one derivatives were identified to inhibit several various proteins and enzymes involved in cancer cell growth, such as topoisomerase, mi-crotubules, protein kinases, phosphoinositide 3-kinases (PI3K) and histone deacetylase (HDAC)...

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function...

Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles...

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs - an effective treatment for lymphomas - has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compound STR-V-53 ( 3 ) showed favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC...

Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity...

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects...

Epigenetic modification shapes differentiation trajectory and regulates the exhaustion state of chimeric antigen receptor T (CAR-T) cells. Limited efficacy induced by terminal exhaustion closely ties with intrinsic transcriptional regulation. However, the comprehensive regulatory mechanisms remain largely elusive. Here, we identify class I histone deacetylase inhibitors (HDACi) as boosters of CAR-T cell function by high-throughput screening of chromatin-modifying drugs, in which M344 and chidamide enhance memory maintenance and resistance to exhaustion of CAR-T cells that induce sustained antitumor efficacy both in vitro and in vivo...

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including the motor neuron disease, amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TDP-43G348C , FUSR521G or SOD1G93A ...

INTRODUCTION: The human host defense peptide LL-37 is a component of the innate immune defense mechanisms of the oral cavity against colonization by microbes associated with periodontal disease. We have previously shown that the active form of vitamin D, 1,25(OH)2 D3 , can induce the expression of LL-37 in gingival epithelial cells (GEC), and prevent the invasion and growth of periopathogenic bacteria in these cells. Further, experimental vitamin D deficiency resulted in increased gingival inflammation and alveolar bone loss...

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice...

Some pregnant women have to experience non-obstetric surgery during pregnancy under general anesthesia. Our previous studies showed that maternal exposure to sevoflurane, isoflurane, propofol, and ketamine causes cognitive deficits in offspring. Histone acetylation has been implicated in synaptic plasticity. Propofol is commonly used in non-obstetric procedures on pregnant women. Previous studies in our laboratory showed that maternal propofol exposure in pregnancy impairs learning and memory in offspring by disturbing histone acetylation...

UNLABELLED: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes...

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile...

ConspectusThe zinc-dependent histone deacetylases (HDACs 1-11) belong to the arginase-deacetylase superfamily of proteins, members of which share a common α/β fold and catalytic metal binding site. While several HDACs play a role in epigenetic regulation by catalyzing acetyllysine hydrolysis in histone proteins, the biological activities of HDACs extend far beyond histones. HDACs also deacetylate nonhistone proteins in the nucleus as well as the cytosol to regulate myriad cellular processes. The substrate pool is even more diverse in that certain HDACs can hydrolyze other covalent modifications...

Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA...

BACKGROUND AND PURPOSE: Kratom is a preparation from Mitragyna speciosa, which is used as a natural drug preparation for many purposes around the world. However, an overdose of Kratom may cause addiction-like problems including aversive withdrawal states resulting in cognitive impairments via unknown mechanisms. Its main psychoactive alkaloid is mitragynine, showing opioid-like properties. EXPERIMENTAL APPROACH: Here, we analysed the neuropharmacological effects of mitragynine compared with morphine withdrawal in rats and searched for a pharmacological treatment option that may reverse the occurring cognitive deficits that usually aggravate withdrawal...

AIM: The class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear. METHODS: In both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis...

Amidst the Zn2+ -dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett's Syndrome, Alzheimer's disease, Huntington's disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases...

The development of cancer is influenced by several variables, including altered protein expression, and signaling pathways. Cancers are inherently heterogeneous and exhibit genetic and epigenetic aberrations; therefore, developing therapies that act on numerous biological targets is encouraged. To achieve this, two approaches are employed: combination therapy and dual/multiple targeting chemotherapeutics. Two enzymes, histone deacetylases (HDACs) and ribonucleotide reductase (RR), are crucial for several biological functions, including replication and repair of DNA, division of cells, transcription of genes, etc...

Oral squamous cell carcinoma (OSCC) is a frequent human malignancy that demonstrates a range of genetic and epigenetic alterations. Histone deacetylases (HDACs) are key epigenetic regulators of cell-cycle progression, differentiation and apoptosis and their dysregulation is implicated in cancer development. HDACs are promising targets for anticancer therapy through the utilisation of HDAC inhibitors (HDACis). OSCC cells have been shown to have low levels of histone acetylation, suggesting that HDACis may produce beneficial effects in patients with OSCC...