Next-generation of selective histone deacetylase inhibitors

Yang, Feifei; Zhao, Na; Ge, Di; Chen, Yi Hua

doi:10.1039/c9ra02985k

Cited by 103 publications

(74 citation statements)

References 138 publications

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“…HDAC8 is one of the essential epigenetic player in cancer progression and overexpresses in different cancer types, including cancers of the colon, breast, lung, gastric, and pancreas, acute myeloid leukemia (AML), and acute lymphocytic leukemia (ALL). Upregulation of HDAC8 inhibited apoptosis and induced cancer cell proliferation [9][10][11][12]. Therefore, targeting HDAC8 could counteract cancer and combat the adverse effects associated with paninhibitors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

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Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K-562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC 50-9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC 50-28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC 50-104.2 μM) and human fibroblasts (HS27) (CC 50-105.0 μM). Thus, among this novel series of TZD *

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Section: Introductionmentioning

confidence: 99%

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Upadhyay

Tilekar

Jänsch³

et al. 2020

Bioorganic Chemistry

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“…HDAC inhibitors can be selective or non-selective (pan-inhibitors) [ 139 ]. HDAC inhibitors can have various toxicities depending on the selectivity of the therapy, the location of the HDAC (e.g., nucleus, cytoplasm, mitochondria), and the tumor type [ 147 ]. The use of non-selective HDAC inhibitors has resulted in severe gastrointestinal and cardiac toxicities.…”

Section: Stimulatory Pathwaysmentioning

confidence: 99%

Immunotherapies targeting stimulatory pathways and beyond

et al. 2021

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Co-stimulatory and co-inhibitory molecules play a critical role in T cell function. Tumor cells escape immune surveillance by promoting immunosuppression. Immunotherapy targeting inhibitory molecules like anti-CTLA-4 and anti-PD-1/PD-L1 were developed to overcome these immunosuppressive effects. These agents have demonstrated remarkable, durable responses in a small subset of patients. The other mechanisms for enhancing anti-tumor activities are to target the stimulatory pathways that are expressed on T cells or other immune cells. In this review, we summarize current phase I/II clinical trials evaluating novel immunotherapies targeting stimulatory pathways and outline their advantages, limitations, and future directions.

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“…In the last decades, increasing evidence has associated epigenetic dysregulation with the development and progression of many diseases, including cancer [ 10 , 11 , 12 ]. For instance, transcriptional upregulation of HDACs was observed in colorectal, pancreatic, lung, gastric, prostate, and ovarian cancer [ 13 , 14 , 15 ]. In particular, HDAC 7 was overexpressed in breast cancer [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

et al. 2020

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Mushrooms can be considered a valuable source of natural bioactive compounds with potential polypharmacological effects due to their proven antimicrobial, antiviral, antitumor, and antioxidant activities. In order to identify new potential anticancer compounds, an in-house chemical database of molecules extracted from both edible and non-edible fungal species was employed in a virtual screening against the isoform 7 of the Histone deacetylase (HDAC). This target is known to be implicated in different cancer processes, and in particular in both breast and ovarian tumors. In this work, we proposed the ibotenic acid as lead compound for the development of novel HDAC7 inhibitors, due to its antiproliferative activity in human breast cancer cells (MCF-7). These promising results represent the starting point for the discovery and the optimization of new HDAC7 inhibitors and highlight the interesting opportunity to apply the “drug repositioning” paradigm also to natural compounds deriving from mushrooms.

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Next-generation of selective histone deacetylase inhibitors

Abstract: Histone deacetylases (HDACs) are clinically validated epigenetic drug targets for cancer treatment.

Cited by 103 publications

References 138 publications

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation

Immunotherapies targeting stimulatory pathways and beyond

Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

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