bims-drucaf Biomed News
on Drugs targeting chromatin associated factor in cancer therapy
Issue of 2020‒08‒09
eight papers selected by
Tian Tian
Vall d’Hebron Institute of Oncology
  1. Domain-selective targeting of BET proteins in cancer and immunological diseases.
  2. Epigenetic alterations as therapeutic targets in Testicular Germ Cell Tumors: current and future application of "epidrugs".
  3. Targeting epigenetic reader domains by chemical biology.
  4. Targeting the Cancer Epigenome with Histone Deacetylase Inhibitors in Osteosarcoma.
  5. Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression.
  6. Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential.
  7. Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors.
  8. PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation.
  1. Curr Opin Chem Biol. 2020 Jul 30. pii: S1367-5931(20)30019-3. [Epub ahead of print]
    Domain-selective targeting of BET proteins in cancer and immunological diseases.
    Massimo Petretich, Emmanuel H Demont, Paola Grandi.
      Cancer and inflammation are strongly interconnected processes. Chronic inflammatory pathologies can be at the heart of tumor development; similarly, tumor-elicited inflammation is a consequence of many cancers. The mechanistic interdependence between cancer and inflammatory pathologies points toward common protein effectors which represent potential shared targets for pharmacological intervention. Epigenetic mechanisms often drive resistance to cancer therapy and immunomodulatory strategies. The bromodomain and extraterminal domain (BET) proteins are epigenetic adapters which play a major role in controlling cell proliferation and the production of inflammatory mediators. A plethora of small molecules aimed at inhibiting BET protein function to treat cancer and inflammatory diseases have populated academic and industry efforts in the last 10 years. In this review, we will discuss recent pharmacological approaches aimed at targeting a single or a subset of the eight bromodomains within the BET family which have the potential to tease apart clinical efficacy and safety signals of BET inhibitors.
    Keywords:  BD1; BD2; BET; Bromodomain; Cancer; Chemical probes; Inflammation; ProTAC; Selectivity
    DOI:  https://doi.org/10.1016/j.cbpa.2020.02.003
  2. Epigenetics. 2020 Aug 04.
    Epigenetic alterations as therapeutic targets in Testicular Germ Cell Tumors: current and future application of "epidrugs".
    Ana Rita Cardoso, João Lobo, Vera Miranda-Gonçalves, Rui Henrique, Carmen Jerónimo.
      Testicular germ cell tumors (TGCTs) are heterogeneous neoplasms mostly affecting young-adult men. Despite high survival rates, some patients with disseminated disease acquire cisplatin resistance, entailing the need for less toxic therapies. Epigenetic alterations constitute an important feature of TGCTs, which are also implicated in resistance mechanism(s). These alterations might be used as potential targets to design epigenetic drugs. To date, several compounds have been explored and evaluated regarding therapeutic efficacy, making use of pre-clinical studies with in vitro and in vivo models, and some have already been explored in clinical trials. This review summarizes the several epigenetic mechanisms at play in these neoplasms, the current challenges in the field of TGCTs and critically reviews available data on "epidrugs" in those tumors.
    Keywords:  Testicular germ cells tumors; epigenetics; histone modifications; methylation; microRNA; targeted therapies
    DOI:  https://doi.org/10.1080/15592294.2020.1805682
  3. Curr Opin Chem Biol. 2020 Jul 30. pii: S1367-5931(20)30071-5. [Epub ahead of print]57 82-94
    Targeting epigenetic reader domains by chemical biology.
    Alessandra Cipriano, Gianluca Sbardella, Alessio Ciulli.
      Over the past years, growing interest toward post-translational modifications (PTMs) of histones and nonhistone proteins has prompted academia and industrial research groups to develop different approaches to better understand the link between PTMs and pathological states. Selective recognition of PTMs is carried out by reader modules, which mediate the biological readout of epigenetic mechanisms. Progress in medicinal chemistry and chemical biology has contributed to corroborate the role of reader domains in chromatin-binding proteins as potential therapeutic targets. Here, we review the state-of-the-art of the most important small molecules developed to date, with a particular attention on contemporary chemical biology approaches, including photoaffinity probes, cyclic peptides, bifunctional inhibitors, and PROTAC degraders.
    Keywords:  Bromodomain; PROTACs; Photo-affinity probes; Post-translational modifications; Reader domains
    DOI:  https://doi.org/10.1016/j.cbpa.2020.05.006
  4. Adv Exp Med Biol. 2020 ;1258 55-75
    Targeting the Cancer Epigenome with Histone Deacetylase Inhibitors in Osteosarcoma.
    Christopher D Collier, Patrick J Getty, Edward M Greenfield.
      Epigenetic deregulation is an emerging hallmark of cancer that enables tumor cells to escape surveillance by tumor suppressors and ultimately progress. The structure of the epigenome consists of covalent modifications of chromatin components, including acetylation by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs). Targeting these enzymes with inhibitors to restore epigenetic homeostasis has been explored for many cancers. Osteosarcoma, an aggressive bone malignancy that primarily affects children and young adults, is notable for widespread genetic and epigenetic instability. This may explain why therapy directed at unique molecular pathways has failed to substantially improve outcomes in osteosarcoma over the past four decades. In this review, we discuss the potential of targeting the cancer epigenome, with a focus on histone deacetylase inhibitors (HDACi) for osteosarcoma. We additionally highlight the safety and tolerance of HDACi, combination chemotherapy with HDACi, and the ongoing challenges in the development of these agents.
    Keywords:  Acetylation; Combination therapy; Epigenetics; Epigenome; HDAC; HDACi; Histone deacetylase inhibitors; KDAC; KDACi; Lysine deacetylase inhibitors; Osteosarcoma; Safety
    DOI:  https://doi.org/10.1007/978-3-030-43085-6_4
  5. Front Immunol. 2020 ;11 1469
    Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression.
    Reem Saleh, Salman M Toor, Varun Sasidharan Nair, Eyad Elkord.
      A balance between co-inhibitory and co-stimulatory signals in the tumor microenvironment (TME) is critical to suppress tumor development and progression, primarily via maintaining effective immunosurveillance. Aberrant expression of immune checkpoints (ICs), including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), can create an immune-subversive environment, which helps tumor cells to evade immune destruction. Recent studies showed that epigenetic modifications play critical roles in regulating the expression of ICs and their ligands in the TME. Reports showed that the promoter regions of genes encoding ICs/IC ligands can undergo inherent epigenetic alterations, such as DNA methylation and histone modifications (acetylation and methylation). These epigenetic aberrations can significantly contribute to the transcriptomic upregulation of ICs and their ligands. Epigenetic therapeutics, including DNA methyltransferase and histone deacetylase inhibitors, can be used to revert these epigenetic anomalies acquired during the progression of disease. These discoveries have established a promising therapeutic modality utilizing the combination of epigenetic and immunotherapeutic agents to restore the physiological epigenetic profile and to re-establish potent host immunosurveillance mechanisms. In this review, we highlight the roles of epigenetic modifications on the upregulation of ICs, focusing on tumor development, and progression. We discuss therapeutic approaches of epigenetic modifiers, including clinical trials in various cancer settings and their impact on current and future anti-cancer therapies.
    Keywords:  DNA methylation; cancer; epigenetics; histone modifications; immune checkpoints; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2020.01469
  6. Front Cell Dev Biol. 2020 ;8 546
    Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential.
    Alexandre Perla, Lívia Fratini, Paula S Cardoso, Carolina Nör, André T Brunetto, Algemir L Brunetto, Caroline Brunetto de Farias, Mariane Jaeger, Rafael Roesler.
      Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.
    Keywords:  brain tumor; ependymoma; epigenetics; glioma; histone deacetylase inhibitors; medulloblastoma
    DOI:  https://doi.org/10.3389/fcell.2020.00546
  7. Eur J Med Chem. 2020 Jul 22. pii: S0223-5234(20)30623-1. [Epub ahead of print]204 112651
    Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors.
    Hao Hu, Fei Chen, Yuhong Dong, Ming Li, Sicong Xu, Mingze Qin, Ping Gong.
      Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC50 of 18.49 nM and remarkable inhibitory activity against c-Met with an IC50 of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC50 values of 0.22 μM, 1.59 μM and 0.22 μM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
    Keywords:  Antitumor activity; HDAC; Synthesis; c-Met
    DOI:  https://doi.org/10.1016/j.ejmech.2020.112651
  8. Sci Rep. 2020 Aug 06. 10(1): 13275
    PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation.
    María F Montenegro, Rebeca González-Guerrero, Luis Sánchez-Del-Campo, Antonio Piñero-Madrona, Juan Cabezas-Herrera, José Neptuno Rodríguez-López.
      The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.
    DOI:  https://doi.org/10.1038/s41598-020-70289-3
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:19:31.