Review
Biochemistry & Molecular Biology
Anna Fontana, Ilaria Cursaro, Gabriele Carullo, Sandra Gemma, Stefania Butini, Giuseppe Campiani
Summary: HDAC8, an important enzyme, plays a role in various diseases and selective HDAC8 inhibitors are being developed. Polypharmacological approaches have also been explored.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Bartosz Bieszczad, Damian Garbicz, Marta Switalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elzbieta Grzesiuk, Adam Mieczkowski
Summary: In this study, a library of 19 analogues of Vorinostat was developed and tested for their HDAC inhibition and cytotoxic effects on cancer and normal cell lines. Three compounds based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds showed better HDAC inhibition and lower IC50 values in leukemic and lymphoma cell lines compared to Vorinostat. These compounds exhibited higher activity and selectivity against specific cancer cell lines and a correlation between HDAC inhibition and cytotoxic effects was observed.
Review
Oncology
Anna Wawruszak, Lidia Borkiewicz, Estera Okon, Wirginia Kukula-Koch, Syeda Afshan, Marta Halasa
Summary: Breast cancer remains a challenging malignancy with varying responses to therapy, requiring the development of new active agents to improve the current treatment regimens. Vorinostat (SAHA) shows promise in the therapy of different histological subtypes of breast cancer, either alone or in combination with other anticancer agents, based on preclinical and clinical trials data.
Review
Biochemistry & Molecular Biology
Svetlana Demyanenko, Valentina Dzreyan, Svetlana Sharifulina
Summary: Cerebral ischemia is the second leading cause of death worldwide, requiring multimodal stroke therapy. Histone deacetylase inhibitors have shown to be effective in protecting the brain from ischemic damage by inducing neurogenesis and angiogenesis in damaged brain areas, promoting functional recovery after stroke.
Article
Biochemistry & Molecular Biology
Justine S. Habibian, Matthew J. Bolino, Bradley S. Ferguson
Summary: Skeletal muscle differentiation requires the activation of satellite cells to proliferate, differentiate, and fuse. This process is regulated by myogenic transcription factors, which are tightly controlled by intracellular signaling pathways, including the protein kinase D (PKD) family. In this study, the researchers found that inhibiting class I histone deacetylases (HDACs), specifically HDAC8, attenuated PKD phosphorylation in skeletal muscle cells, suggesting that HDAC8 may function as a feedback regulator of PKD phosphorylation during muscle differentiation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Review
Cell Biology
Bingyi Zhou, Deliang Liu, Yuyong Tan
Summary: Cancer is the second leading cause of death worldwide, with digestive system cancers being a primary contributor. Acetylation and deacetylation play crucial roles in cancer development, with HDAC6 being a widely studied enzyme that is upregulated in various tumors and associated with clinicopathological characteristics. There is ongoing research on HDAC6 inhibitors and their potential in inhibiting tumor growth.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Negar Omidkhah, Razieh Ghodsi
Summary: NO-HDAC dual inhibitors have demonstrated satisfactory therapeutic effects in various diseases and possess high therapeutic potential.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Sk Abdul Amin, Samima Khatun, Shovanlal Gayen, Sanjib Das, Tarun Jha
Summary: HDAC8 is an enzyme that aberrantly deacetylates histone and non-histone proteins, regulating processes such as leukemic stem cell transformation and maintenance. In solid and hematological cancer progressions, especially AML and ALL, HDAC8 affects the gene silencing process. A specific HDAC8 inhibitor, PCI-34051, has shown promising results against T-cell lymphoma and AML. This article summarizes the role of HDAC8 in hematological malignancies, particularly in AML and ALL, and addresses the selectivity issue of HDAC8 enzyme in hematological cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Nils Goehringer, Yayi Peng, Bianca Nitzsche, Hannah Biermann, Rohan Pradhan, Rainer Schobert, Marco Herling, Michael Hoepfner, Bernhard Biersack
Summary: The development of new anticancer drugs is essential due to the limitations of current drugs. Histone deacetylases (HDACs) have emerged as promising targets for cancer treatment. SF5-SAHA, a newly synthesized HDAC inhibitor, showed strong inhibition of tumor cell growth and potential for further development as an anticancer drug candidate.
Article
Oncology
Roisin M. Connolly, Fengmin Zhao, Kathy D. Miller, Min-Jung Lee, Richard L. Piekarz, Karen L. Smith, Ursa A. Brown-Glaberman, Jennifer S. Winn, Bryan A. Faller, Adedayo A. Onitilo, Mark E. Burkard, George T. Budd, Ellis G. Levine, Melanie E. Royce, Peter A. Kaufman, Alexandra Thomas, Jane B. Trepel, Antonio C. Wolff, Joseph A. Sparano
Summary: The combination of entinostat and exemestane did not improve survival in patients with AI-resistant advanced HR-positive, HER2-negative breast cancer. E2112 phase III trial: no benefit seen in adding HDAC inhibitor entinostat to exemestane in advanced breast cancer.
JOURNAL OF CLINICAL ONCOLOGY
(2021)
Article
Engineering, Environmental
Jian-Li Chen, Xiao-Hui Jia, Xinyue Xia, Xuan Wu, Yan-Neng Xu, Gang Yuan, Ze-Yun Gu, Kathy Qian Luo, Ming-Heng Yuan, Ruibin Jiang, Jianfang Wang, Xiao-Ming Zhu
Summary: In this study, hollow ZrO2 nanoshells were synthesized to encapsulate both the autophagy inhibitor chloroquine (CQ) and the HDAC inhibitor vorinostat (Vor) for effective combinational cancer therapy. The ZrO2 nanoshells showed high loading capacities for both CQ and Vor and exhibited a controlled release profile. The codelivery system enhanced the autophagy inhibition and hyperacetylation level in the cells, resulting in a superior antitumor effect in 4T1 tumor-bearing mice.
CHEMICAL ENGINEERING JOURNAL
(2023)
Article
Neurosciences
Paulina Misztak, Magdalena Sowa-Kucma, Bernadeta Szewczyk, Gabriel Nowak
Summary: The study evaluated the impact of SAHA on the expression of several key proteins in the brain's signal transduction pathways, as well as the concentration of the oxidative stress product MDA. SAHA may prevent oxidative stress by decreasing MDA concentration and increasing p-AMPK expression, while also boosting neuroprotective and antidepressant protein levels.
NEUROTOXICITY RESEARCH
(2021)
Article
Chemistry, Medicinal
Liang Xing, Guoliang Gong, Xinyang Chen, Xin Chen
Summary: A series of aroylpiperazine hybrid derivatives were synthesized and tested for their activity against HDAC1. Indole-piperazine hybrids 6a (IC50 = 205 nM) and 6b (IC50 = 280 nM) exhibited submicromolar activity against HDAC1. Specifically, 6a showed strong affinity towards class I HDACs, particularly HDAC1-3. In vitro, 6a showed better antiproliferative activity against K562 and HCT116 cell lines compared to chidamide.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2023)
Article
Cell Biology
Yong Wang, Fen Liu, Chen Fang, Liyao Xu, Lin Chen, Zeyao Xu, Jiaquan Chen, Wei Peng, Biqi Fu, Yong Li
Summary: The combination treatment of RAPA and SAHA significantly enhances the inhibitory effect of radiotherapy on NSCLC, primarily by modulating the expression of DNA damage proteins and increasing radiotherapy sensitivity. This combined therapy also effectively inhibits tumor growth in the A549 xenograft model.
Review
Pharmacology & Pharmacy
Yvonne E. Klingl, Donya Pakravan, Ludo Van den Bosch
Summary: ALS is a devastating neurodegenerative disease with limited treatment options. Research suggests that interference with histone deacetylases may be helpful in treating ALS.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mohammed K. AbdElhameid, Madlen B. Labib, Ahmed T. Negmeldin, Muhammad Al-Shorbagy, Manal R. Mohammed
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2018)
Article
Biochemistry & Molecular Biology
Dhanusha A. Nalawansha, Yuchen Zhang, Kavinda Herath, Mary Kay H. Pflum
ACS CHEMICAL BIOLOGY
(2018)
Article
Chemistry, Multidisciplinary
Satish Garre, Aparni K. Gamage, Todd R. Faner, Pavithra Dedigama-Arachchige, Mary Kay H. Pflum
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2018)
Article
Biochemistry & Molecular Biology
Inosha D. Gomes, Mary Kay H. Pflum
Article
Biochemistry & Molecular Biology
Nuwan P. N. Acharige, Mary Kay H. Pflum
Summary: Kinases and phosphatases play important roles in cellular signaling, with aberrant activity potentially leading to diseases. Phosphatases are less studied due to limited substrate identification methods. The development of K-BIPS provides a new tool to explore phosphatase biology by identifying unexpected substrates.
Article
Chemistry, Multidisciplinary
Ahmed E. Fouda, Aparni K. Gamage, Mary Kay H. Pflum
Summary: A new affinity-based crosslinking ATP analog, ATP-MAc, has been developed to covalently link kinases containing cysteines in the active site with their substrates. This method avoids the challenges posed by UV light irradiation and non-specific reactivity, providing a new tool for studying signaling cascades in normal and diseased states.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Inosha D. Gomes, Udana Ariyaratne, Mary Kay H. Pflum
Summary: HDAC6 is upregulated in various tumor cell lines and plays roles in cell signaling, protein degradation, and other cellular processes. The study utilized substrate trapping mutants to identify PRMT5 as a novel substrate of HDAC6, revealing potential crosstalk between acetylation and methylation. Substrate trapping is a powerful and unbiased approach to discover substrates of HDAC6.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biochemical Research Methods
Vindya Ramanayake-Mudiyanselage, D. Maheeka Embogama, Mary Kay H. Pflum
Summary: Cell signaling involves a complex network of protein interactions and post-translational modifications. The K-BMAPS method, utilizing ATP-biotin to label substrates, is a powerful tool for mapping dynamic phosphorylation in cell signaling pathways. This method has been used successfully to study the EGFR pathway and identify key phosphoproteins associated with late and continuous signaling events.
JOURNAL OF PROTEOME RESEARCH
(2021)
Review
Medicine, Research & Experimental
Dana Elkhalifa, Menatallah Rayan, Ahmed T. Negmeldin, Abdelbary Elhissi, Ashraf Khalil
Summary: Chemically modified mRNA is a promising approach for producing biopharmaceutical agents, with applications in addressing epidemics and treating a variety of chronic diseases, such as metabolic disorders, cancer, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Biochemical Research Methods
Rachel J. Beltman, Andrew A. Herppich, Hannah J. Bremer, Mary Kay H. Pflum
Summary: Phosphorylation of proteins by kinase enzymes plays a crucial role in cell signaling and disease development. Identifying the interactions between kinases and their phosphorylated substrates is important for understanding cellular events and developing kinase-targeting drugs. In this study, we introduce two ATP analogues, ATP-AFS and ATP-HexBr, which can crosslink kinase-substrate pairs without the need for UV irradiation. Both ATP-AFS and ATP-HexBr showed efficient crosslinking, with ATP-AFS demonstrating more robust complexes. Importantly, ATP-AFS can promote crosslinking in complex cellular mixtures, allowing for future applications in kinase-substrate identification.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Yuchen Zhang, Dhanusha A. Nalawansha, Kavinda E. Herath, Rafael Andrade, Mary Kay H. Pflum
Summary: Histone deacetylase (HDAC) proteins, which regulate the acetylation state of proteins, have different roles in the progression of various cancer types and show distinct effects in breast cancer cells. Comparing the associated protein profiles of HDAC1 in different breast cancer cell lines revealed variable roles indicating potential impact on cancer aggressiveness and drug sensitivity.
Article
Pharmacology & Pharmacy
Marianne Joseph Naguib, Amira Moustafa Kamel, Ahmed Thabet Negmeldin, Ahmed Hassen Elshafeey, Ibrahim Elsayed
Article
Biochemistry & Molecular Biology
Pavithra M. Dedigama-Arachchige, Nuwan P. N. Acharige, Mary Kay H. Pflum
Article
Chemistry, Medicinal
Shuang Mei, Su Jiang, Yuting Wang, Han Jing, Peng Yang, Miao-Miao Niu, Jindong Li, Kai Yuan, Yan Zhang
Summary: This study identifies a dual-targeting peptide, AP-1, that effectively inhibits variants of concern (VOCs) of SARS-CoV-2 without impairing host cell viability. The findings suggest that AP-1 could be a promising broad-spectrum agent for treating emerging VOCs of SARS-CoV-2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Hyeonjun Lee, Ju Yeon Lee, Hyunsoo Jang, Hye Young Cho, Minhee Kang, Sang Hyun Bae, Suin Kim, Eunji Kim, Jaebong Jang, Jin Young Kim, Young Ho Jeon
Summary: By using liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance experiments, we identified new chemical moieties that bind to the target sites of the protein of interest, allowing for reversible binding and protein degradation. This method has the potential to expand the application of PROTAC technology.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Yingying Li, Xiyou Du, Xinru Kong, Yuelin Fang, Zhijing He, Dongzhu Liu, Hang Wu, Jianbo Ji, Xiaoye Yang, Lei Ye, Guangxi Zhai
Summary: This study proposes a novel nanoplatform based on the autophagy cascade to overcome the obstacles in chemo-immunotherapy. The platform combines chemotherapy and starvation therapy to initiate pro-death autophagy and enhance antigen presentation, while also remodeling the immunosuppressive tumor microenvironment. Furthermore, the study discovers a new therapeutic direction for the respiration inhibitor 3-bromopyruvic acid (3BP) in cancer treatment. Overall, this study offers an opportunity to improve antitumor efficacy and boost immune responses.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Bingsi Wang, Mingxu Ma, Yusen Dai, Pengfei Yu, Liang Ye, Wenyan Wang, Chunjie Sha, Huijie Yang, Yingjie Yang, Yunjing Zhu, Lin Dong, Shujuan Wei, Linlin Wang, Jingwei Tian, Hongbo Wang
Summary: Breast cancer is a common malignant tumor in women, and drug resistance remains a clinical challenge. In this study, a novel compound, G-5b, was developed with potent antagonistic and degradation activities comparable to the current drug fulvestrant. G-5b also showed improved stability and solubility. Mechanistically, G-5b engages the proteasome pathway to degrade ER, inhibiting the ER signaling pathway and inducing apoptosis and cell cycle arrest. In animal models, G-5b exhibited superior pharmacokinetics and pharmacodynamics properties. Overall, G-5b is a promising long-acting SERD worthy of further investigation and optimization.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Michal Sulik, Diana Fontinha, Dietmar Steverding, Szymon Sobczak, Michal Antoszczak, Miguel Prudencio, Adam Huczynski
Summary: This study describes the synthesis of the first-in-class ivermectin derivatives obtained through derivatization of the C13 position, along with the unexpected rearrangement of the macrolide ring. These derivatives show potential for antiparasitic activity and are important for the development of new antiparasitic agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Jun Liu, Qiu-Xian Chen, Wen-Fu Wu, Dong Wang, Si -Yu Zhao, Jia-Hao Li, Yi-Qun Chang, Shao-Gao Zeng, Jia-Yi Hu, Yu-Jie Li, Jia-Xin Du, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai -Bo Zhou, Yong-Heng Wang, Jian Zou, Ping-Hua Sun
Summary: A new anti-infective drug strategy has been discovered to attenuate virulence and modulate inflammation caused by drug-resistant Pseudomonas aeruginosa infections. Compound 5f inhibits biofilm formation, macrophage migration, and inflammatory response induced by P. aeruginosa, showing potential as a novel candidate against drug-resistant infections.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Liuzeng Chen, Ke Wang, Lingyun Wang, Wei Wang, Lifan Wang, Jia Li, Xiaohan Liu, Mengya Wang, Banfeng Ruan
Summary: In this study, a series of novel anti-inflammatory compounds were designed and synthesized based on the natural product pterostilbene skeleton. Among them, compound 8 showed the highest activity and exhibited its effects through inhibition of pro-inflammatory cytokines by blocking the NF-KB/MAPK signaling pathway. Compound 8 also demonstrated a good relieving effect on acute colitis in mice and showed good safety in acute toxicity experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)
Article
Chemistry, Medicinal
Si-Min Liang, Gui-Bin Liang, Hui-Ling Wang, Hong Jiang, Xian-Li Ma, Jian-Hua Wei, Ri-Zhen Huang, Ye Zhang
Summary: A series of novel multi-target antitumor agents were designed, synthesized, and evaluated. Some compounds exhibited significant antitumor activity and one compound showed excellent efficacy, limited toxicity, and low resistance. Further mechanism studies revealed that the compound exerted antitumor effects through multiple pathways.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)