作者: Ferraguti, Giampiero ; Micangeli, Ginevra ; Ceccanti, Mauro ; Fiore, Marco ; Terracina, Sergio ; Fuso, Andrea ; Lucarelli, Marco ; Fanfarillo, Francesca ; Tarani, Luigi

Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.

2024-09-01·BIOMATERIALS

Hypoxia-accelerating pyroptosis nanoinducers for promoting image-guided cancer immunotherapy

Article

作者: Li, Wen ; Liang, Mengyun ; Liu, Dongfang ; Tao, Yongyou ; Liu, Qian ; Bing, Wei ; Qi, Ji ; Liu, Hanwen

Precise image-guided cancer immunotherapy holds immense potential in revolutionizing cancer treatment. The strategies facilitating activatable imaging and controlled therapeutics are highly desired yet to be developed. Herein, we report a new pyroptosis nanoinducer that integrates aggregation-induced emission luminogen (AIEgen) and DNA methyltransferase inhibitor with hypoxia-responsive covalent organic frameworks (COFs) for advanced image-guided cancer immunotherapy. We first synthesize and compare three donor-acceptor type AIEgens featuring varying numbers of electron-withdrawing units, and find that the incorporation of two acceptors yields the longest response wavelength and most effective photodynamic therapy (PDT) property, surpassing the performance of analogs with one or three acceptor groups. A COF-based nanoplatform containing AIEgen and pyroptosis drug is successfully constructed via the one-pot method. The intra-COF energy transfer significantly quenches AIEgen, in which both fluorescence and PDT properties greatly enhance upon hypoxia-triggered COF degradation. Moreover, the photodynamic process exacerbates hypoxia, accelerating pyroptosis drug release. The nanoagent enables sensitive delineation of tumor site through in situ activatable fluorescence signature. Thanks to the exceptional ROS production capabilities and hypoxia-accelerating drug release, the nanoagent not only inhibits primary tumor growth but also impedes the progression of distant tumors in 4T1 tumor-bearing mice through potent pyroptosis-mediated immune response. This research introduces a novel strategy for achieving activatable phototheranostics and self-accelerating drug release for synergetic cancer immunotherapy.

2024-09-01·Journal of biomolecular structure & dynamics

Exploring epigenetic drugs as potential inhibitors of SARS-CoV-2 main protease: a docking and MD simulation study.

Article

作者: Akkus, Ebru ; Kocak, Abdulkadir ; Uzuner, Ugur ; Çelik Uzuner, Selcen

The COVID-19 pandemic has caused havoc around the globe since 2019 and is considered the largest global epidemic of the twentieth century. Although the first antiviral drug, Remdesivir, was initially introduced against COVID‑19, virtually no tangible therapeutic drugs exist to treat SARS-CoV-2 infection. FDA-approved Paxlovid (Nirmatrelvir supplemented by Ritonavir) was recently announced as a promising drug against the SARS-CoV-2 major protease (M^pro). Here we report for the first time the remarkable inhibitory potentials of lead epigenetic-targeting drugs (epi-drugs) against SARS-CoV-2 M^pro. Epi-drugs are promising compounds to be used in combination with cancer chemotherapeutics to regulate gene expression. The search for all known epi-drugs for the specific inhibition of SARS-CoV-2 M^pro was performed for the first time by consensus (three high-order program) molecular docking studies and end-state free energy calculations. Several epi-drugs were identified with highly comparable binding affinity to SARS-CoV-2 M^pro compared to Nirmatrelvir. In particular, potent histone methyltransferase inhibitor EPZ005687 and DNA methyltransferase inhibitor Guadecitabine were prominent as the most promising epi-drug inhibitors for SARS-CoV-2 M^pro. Long Molecular dynamics (MD) simulations (200 ns each) and corresponding MM-GBSA calculations confirmed the stability of the EPZ005687-M^pro complex with MM-GBSA binding free energy (ΔG_bind) -48.2 kcal/mol (EPZ005687) compared to Nirmatrelvir (-44.7 kcal/mol). Taken together, the antiviral activities of the highlighted epi-drugs are reported beyond widespread use in combination with anti-cancer agents. The current findings therefore highlight as yet unexplored antiviral potential of epi-drugs suitable for use in patients struggling with chronic immunosuppressive disorders.Communicated by Ramaswamy H. Sarma.

项与 QTX-200 series (Quimatryx) 相关的新闻（医药）

2023-11-17

·BioSpace

Taiho Oncology and Astex Pharmaceuticals Announce Data Presentations at the 65th ASH Annual Meeting

[17-November-2023] Real-world evidence on use of oral decitabine and cedazuridine in the treatment of myelodysplastic syndromes to be featured in an oral presentation; results of several additional studies in hematological malignancies were accepted for poster presentations PRINCETON, N.J. and PLEASANTON, Calif., Nov. 17, 2023 /PRNewswire/ -- Taiho Oncology Inc. and Astex Pharmaceuticals, Inc. announced today details of studies to be presented at the 65th American Society of Hematology (ASH) Annual Meeting, to be held Dec. 9-12, 2023, in San Diego. Among these data are the results of a real-world study of oral decitabine and cedazuridine in patients with myelodysplastic syndromes (MDS), which will be featured in an oral presentation. "Real-world data in healthcare is invaluable as it provides us with a closer look at actual patient experiences outside the clinical trial setting," said Tehseen Salimi, MD, MHA, Senior Vice President Medical Affairs, Taiho Oncology. "This study is the first to explore how an oral therapy may help patients with MDS adhere to their treatment regimen, while reducing both personal and disease burden. Oral decitabine and cedazuridine is a potentially important treatment option for people living with this form of cancer." Below are viewing details of this oral presentation. The above study was sponsored by Taiho Oncology. In addition, investigational compounds from Astex Pharmaceuticals that are currently in various stages of clinical development will be featured in several poster presentations. The above studies are being sponsored by Astex Pharmaceuticals, Inc. About Taiho Oncology, Inc. The mission of Taiho Oncology, Inc. is to improve the lives of patients with cancer, their families and their caregivers. The company specializes in the development and commercialization of orally administered anti-cancer agents for various tumor types. Taiho Oncology has a robust pipeline of small molecule clinical candidates targeting solid tumor and hematological malignancies, with additional candidates in pre-clinical development. Taiho Oncology is a subsidiary of Taiho Pharmaceutical Co., Ltd. which is part of Otsuka Holdings Co., Ltd. Taiho Oncology is headquartered in Princeton, New Jersey and oversees its parent company's European and Canadian operations, which are located in Zug, Switzerland and Oakville, Ontario, Canada. For more information, visit , and follow us on LinkedIn and Twitter. About Astex Pharmaceuticals, Inc. Astex Pharmaceuticals, Inc. is committed to the fight against cancer. Astex is developing a proprietary pipeline of novel therapies for the treatment of solid tumors and hematological malignancies. Astex is a member of the Otsuka group of companies. The group also includes Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Taiho Oncology, Inc. Astex, the Astex logo, Taiho Oncology, and the Taiho Oncology logo are registered trademarks of Otsuka Holdings Co., Ltd. or its subsidiaries. Taiho Oncology Contact: Judy Kay Moore (574) 526-2369 jumoore@taihooncology.com Astex Pharmaceuticals: Martin Buckland Astex Pharmaceuticals, Inc. (+1) 925-560-0100 martin.buckland@astx.com INQ-PM-US-0512 1 Investigational Oral DNA Methyltransferase Inhibitor 2 X-Linked Inhibitor of Apoptosis Protein (XIAP)/Cellular Inhibitor of Apoptosis Protein (cIAP) Antagonist - Astex Pharmaceuticals, Inc. investigational agent being developed in collaboration with Taiho Oncology, Inc.

ASH会议

2023-09-11

·Endpoints

Gilead, AstraZeneca/Daiichi Sankyo offer first look at TROP2 ADCs in first-line lung cancer as rivalry heats up

Preliminary mid-stage data from two rival TROP2-targeting ADCs advanced by AstraZeneca/Daiichi Sankyo and Gilead, combined with immune checkpoint inhibitors, have provided a first glance at the risk-benefit balance of this approach in non-small cell lung cancer. And although Gilead noticed a slightly higher response rate, analysts called the results “broadly similar.” Both AstraZeneca’s Dato-DXd and Gilead’s Trodelvy comprise an antibody that targets the TROP2 receptor linked with a DNA topoisomerase 1 inhibitor. Dato-DXd is an investigational program in Phase III for breast cancer and NSCLC, while Trodelvy is approved as a single agent for certain forms of breast cancer and has won accelerated approval for bladder cancer.

抗体药物偶联物临床3期上市批准加速审批

100 项与 QTX-200 series (Quimatryx) 相关的药物交易

登录后查看更多信息