Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

Zang, Lanlan; Kondengaden, Shukkoor Muhammed; Zhang, Qing; Li, Xiaobo; Sigalapalli, Dilep Kumar; Kondengadan, Shameer M.; Huang, Kenneth; Li, Keqin Kathy; Li, Shanshan; Xiao, Zhongying; Wen, Liuqing; Zhu, Hai‐Liang; Babu, Bathini Nagendra; Wang, Limin; Che, Fengyuan; Wang, Peng George

doi:10.18632/oncotarget.18730

Cited by 29 publications

(11 citation statements)

References 52 publications

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“…It is worth noting that no post-translational modifications processes exist in isolation but rather act with mutual influence and coordination, usually referred to as histone crosstalk. In our earlier research (Zang et al, 2017 ), we found that simultaneously inhibiting the activity of HDAC and G9a would yield better effects than inhibiting single targets. In our anti-proliferation experiment, multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma and breast carcinoma were used in this study.…”

Section: Histone Modificationsmentioning

confidence: 74%

Potential Epigenetic-Based Therapeutic Targets for Glioma

Zang

Kondengaden

Che

et al. 2018

Front. Mol. Neurosci.

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Glioma is characterized by a high recurrence rate, short survival times, high rates of mortality and treatment difficulties. Surgery, chemotherapy and radiation (RT) are the standard treatments, but outcomes rarely improve even after treatment. With the advancement of molecular pathology, recent studies have found that the development of glioma is closely related to various epigenetic phenomena, including DNA methylation, abnormal microRNA (miRNA), chromatin remodeling and histone modifications. Owing to the reversibility of epigenetic modifications, the proteins and genes that regulate these changes have become new targets in the treatment of glioma. In this review, we present a summary of the potential therapeutic targets of glioma and related effective treating drugs from the four aspects mentioned above. We further illustrate how epigenetic mechanisms dynamically regulate the pathogenesis and discuss the challenges of glioma treatment. Currently, among the epigenetic treatments, DNA methyltransferase (DNMT) inhibitors and histone deacetylase inhibitors (HDACIs) can be used for the treatment of tumors, either individually or in combination. In the treatment of glioma, only HDACIs remain a good option and they provide new directions for the treatment. Due to the complicated pathogenesis of glioma, epigenetic applications to glioma clinical treatment are still limited.

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Section: Histone Modificationsmentioning

confidence: 74%

Potential Epigenetic-Based Therapeutic Targets for Glioma

Zang

Kondengaden

Che

et al. 2018

Front. Mol. Neurosci.

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“…Moreover, this compound shows good pharmacokinetic properties in vivo [82]. Structure-based design, synthesis, and screening of small molecules for dual inhibitory activity of G9a and histone deacetylases (HDACs) allowed for the discovery of compound 14, which inhibits both enzymes in the low micromolar range in cell-based platforms [83]. Structure-based approaches also led to the design and synthesis of reversible chemical probes that inhibit both G9a and DNMTs at nanomolar ranges, resulting in compounds with in vitro antiproliferative activities in the nanomolar range and tumor growth inhibition in a human acute myeloid leukemia mouse model [84].…”

Section: Drug Development Of G9a Inhibitors For Cancer Therapymentioning

confidence: 99%

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

Souza

Freire

Jaeger

et al. 2021

IJMS

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Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

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“…Merging the quinazoline scaffold typical of BIX01294 97 with polymethylene hydroxamate chains allowed the identification of dual G9a/HDAC inhibitors. Among them, 102 (Figure ) showed low toxicity, good physico‐chemical properties, and antiproliferative activity in the micromolar range in HeLa and K562 cell lines …”

Section: The Mtdl Approachmentioning

confidence: 99%

“…Among them, 102 ( Figure 11) showed low toxicity, good physico-chemical properties, and antiproliferative activity in the micromolar range in HeLa and K562 cell lines. 378,379 As previously discussed, G9a plays a key role in melanoma, breast and lung cancer mediating cellular growth and regulating cell cycle and metabolism pathways. 380 Another KMT, the H3K27 methyltransferase EZH2, has a repressive role in gene expression and has been found mutated in BCL and upregulated in breast and prostate carcinoma.…”

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confidence: 92%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

Cited by 29 publications

References 52 publications

Potential Epigenetic-Based Therapeutic Targets for Glioma

Potential Epigenetic-Based Therapeutic Targets for Glioma

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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