Review
Biochemistry & Molecular Biology
Estelle Deboever, Alessandra Fistrovich, Christopher Hulme, Travis Dunckley
Summary: With the increasing aging population, finding therapeutic solutions for age-related diseases becomes crucial. Kinases play a pivotal role in human health and represent promising targets for drug development. DYRK1A, a protein implicated in various human diseases, has attracted significant attention for its potential therapeutic applications.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Cheng Ju, Yue Wang, Caixia Zang, Hui Liu, Fangyu Yuan, Jingwen Ning, Meiyu Shang, Jingwei Ma, Gen Li, Yang Yang, Xiuqi Bao, Dan Zhang
Summary: This study investigated the role of Dyrk1A in regulating neuroinflammation and found that inhibiting Dyrk1A can reduce neuroinflammation and the production of proinflammatory factors.
Review
Chemistry, Medicinal
Priya Singh, Deepika Singh, Pooja Srivastava, Gauri Mishra, Anjani K. K. Tiwari
Summary: The lack of information about in vivo impairments and tools for assessing brain penetrance and efficiency of newly designed drugs has hindered the development of treatments for new central nervous system diseases.
DRUG DEVELOPMENT RESEARCH
(2023)
Review
Pharmacology & Pharmacy
Feng-Dan Zhu, Yu-Jiao Hu, Lu Yu, Xiao-Gang Zhou, Jian-Ming Wu, Yong Tang, Da-Lian Qin, Qing-Ze Fan, An-Guo Wu
Summary: Neuroinflammation is a common feature of neurodegenerative diseases, and inhibiting the over-activation of microglia is a promising approach for treatment.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Xiaoyu Song, Wanfu Wu, Margaret Warner, Jan-Ake Gustafsson
Summary: This review discusses the role of liver X receptors (LXRs) in glial cells in the central nervous system (CNS). LXRs regulate genes involved in cholesterol homeostasis, inflammatory responses, and glutamate homeostasis. Studies on LXR knockout mice have shown that LXR beta is crucial for the health of various types of neurons in both CNS and peripheral nervous system. LXRs are also important for cerebrospinal fluid homeostasis. Despite the neurological deficits observed in LXR-deficient rodents, defective LXR signaling has only been identified in multiple sclerosis among human neurodegenerative diseases. Targeting LXRs in glial cells may hold potential for treating neurodegenerative diseases and disorders caused by abnormal neuronal migration during development.
Review
Biochemistry & Molecular Biology
Andrea Baier, Ryszard Szyszka
Summary: Casein kinases are important factors in signaling pathways, inflammation, cancer, and neurological diseases, making them potential therapeutic targets. Recent studies have shown that the casein kinase 1 superfamily and CK2 play significant roles in the development of neurodegenerative pathologies. Overexpression of these kinases in the brain is closely related to neuronal and synaptic network functions. Therefore, the development of new substances for the treatment of these diseases is crucial.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Cardiac & Cardiovascular Systems
Alexander Young, Leigh A. Bradley, Elizabeth Farrar, Helen O. Bilcheck, Svyatoslav Tkachenko, Jeffrey J. Saucerman, Stefan Bekiranov, Matthew J. Wolf
Summary: Inhibition of DYRK1a improves cardiac function and promotes cycling cardiomyocytes after myocardial infarction, suggesting it as a potential therapeutic target for treating MI.
CIRCULATION RESEARCH
(2022)
Article
Neurosciences
Yu-Tzu Shih, Jason Bondoc Alipio, Amar Sahay
Summary: Heterozygous mutations in the Dyrk1a gene can cause a syndromic form of autism spectrum disorder. This study reveals the synaptic and circuit mechanisms behind Dyrk1a's role in social cognition, showing that DYRK1A recruits feedforward inhibition of CA3 and CA2 through ABLIM3 to promote social recognition. Restoring Ablim3 levels can reverse circuit and cognition impairments associated with Dyrk1a haploinsufficiency.
Review
Neurosciences
Gianfranco Natale, Fiona Limanaqi, Carla L. Busceti, Federica Mastroiacovo, Ferdinando Nicoletti, Stefano Puglisi-Allegra, Francesco Fornai
Summary: Recent studies on nervous lymphatic drainage and the blood-brain barrier have revealed a glymphatic pathway in the brain, similar to the peripheral lymphatic system. This pathway allows for the clearance of waste products from the brain, challenging the classic concept of the brain's immune privilege. Research is also exploring the potential role of the glymphatic pathway in neurodegenerative diseases and other acute neurological disorders.
FRONTIERS IN NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Csaba Weber, Melinda Sipos, Attila Paczal, Balazs Balint, Vilibald Kun, Nicolas Foloppe, Pawel Dokurno, Andrew J. Massey, David Lee Walmsley, Roderick E. Hubbard, James Murray, Karen Benwell, Thomas Edmonds, Didier Demarles, Alain Bruno, Mike Burbridge, Francisco Cruzalegui, Andras Kotschy
Summary: The kinase DYRK1A has been identified as a promising target for drug discovery, and a biaryl compound was developed through fragment screening to efficiently bind to its ATP site. Structural optimization cycles resulted in the transformation of this compound into potent and selective DYRK1A inhibitors, with a focus on fine-tuning selectivity by exploiting structural differences with DYRK2. These inhibitors demonstrated potent inhibition of DYRK1A in cell culture and in vivo, with drug-like properties and dose-dependent tumor growth inhibition in an ovarian carcinoma model.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Teresa de los Reyes Corrales, Maria Losada-Perez, Sergio Casas-Tinto
Summary: The JNK signaling pathway is crucial in the central nervous system, playing a central role in combating pathophysiological insults during development and adulthood. It is involved in various diseases such as glioblastoma, regeneration/repair after injury, neurodegeneration, and neuronal cell death.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Psychiatry
Jean M. Delabar, Julien Lagarde, Marta Fructuoso, Ammara Mohammad, Michel Bottlaender, Eric Doran, Ira Lott, Isabelle Rivals, Frederic A. Schmitt, Elizabeth Head, Marie Sarazin, Marie-Claude Potier
Summary: Early markers for effective prevention of Alzheimer's disease are important. Plasma DYRK1A levels were found to be decreased in individuals with Alzheimer's disease compared to controls. DYRK1A levels were inversely correlated with brain amyloid beta burden in asymptomatic elderly individuals and Alzheimer's disease patients, and low levels were also found in patients with tauopathies. Higher DYRK1A levels were observed in individuals with Down syndrome, but lower levels were found in individuals with Down syndrome and dementia. These findings suggest that plasma DYRK1A levels could serve as early detection markers for individuals at risk of Alzheimer's disease.
TRANSLATIONAL PSYCHIATRY
(2023)
Review
Pharmacology & Pharmacy
Yuping Yang, Xiaoxiao Fan, Yongjian Liu, Danyang Ye, Cen Liu, Hongliu Yang, Zhijun Su, Yuanyuan Zhang, Yonggang Liu
Summary: DYRK1A is an evolutionarily conserved protein kinase and the most studied member of the DYRK family. It plays a role in the development of various diseases, and both low or high expression of DYRK1A protein can lead to disorder. It is recognized as a key target for therapy, and the studies on its natural and synthetic inhibitors have become increasingly popular.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Cell Biology
Pin Wang, Juan Zhao, Xiulian Sun
Summary: Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) was found to phosphorylate MEF2D at Ser251, leading to increased MEF2D protein level but decreased transcriptional activity, which in turn resulted in reduced expression of MEF2D target genes. This interaction between DYRK1A and MEF2D may play a role in regulating gene expression.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2021)
Article
Biology
Lydia B. Zablotska, Ljubica Zupunski, Klervi Leuraud, Julie Lopes, Joshua Hinkle, Tyler Pugeda, Thomas Delgado, John Olschowka, Jacqueline Williams, M. Kerry O'Banion, John D. Boice, Sarah S. Cohen, Michael T. Mumma, Lawrence T. Dauer, Richard A. Britten, Samuel Stephenson, Klervi Leuraud, Julie Lopes, Joshua Hinkle, Tyler Pugeda, Thomas Delgado, John Olschowka, Jacqueline Williams, M. Kerry O'Banion, John D. Boice, Sarah S. Cohen, Michael T. Mumma, Lawrence T. Dauer, Richard. A. Britten, Samuel Stephenson
Summary: This article summarizes a virtual symposium on the radiation risks of the central nervous system. It discusses the potential neurological complications and psychological consequences of repeated low-dose radiation exposure, emphasizing the need for further research in this area. The symposium highlights new directions for studying mental health disorders, neurodegenerative conditions, and cognitive impairment related to radiation exposure, including occupational exposures and exposures to galactic cosmic rays.
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY
(2023)
Review
Chemistry, Medicinal
Ahmed K. ElHady, Dalia S. El-Gamil, Ashraf H. Abadi, Mohammad Abdel-Halim, Matthias Engel
Summary: Clk1 has been identified as a promising target for the treatment of various diseases, especially those related to deregulated alternative splicing. Clinical trials of small molecule inhibitors targeting Clk1 are underway for the treatment of solid cancer, which is promoted by oncogenic protein variants derived from alternative splicing. In addition, Clk1 has been implicated in the progression of Alzheimer's disease. However, most Clk1 inhibitors lack sufficient selectivity, affecting other Clk isoforms and Dyrk kinases.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Chemistry, Medicinal
Dalia S. El-Gamil, Ahmed K. ElHady, Po-Jen Chen, Tsong-Long Hwang, Ashraf H. Abadi, Mohammad Abdel-Halim, Matthias Engel
Summary: Clk1 kinase is a key modulator of pre-mRNA alternative splicing and could be a potential target for treating various tumors, Duchenne's muscular dystrophy, and viral infections. A new 5-methoxybenzothiophene scaffold was developed, enabling selective inhibition of Clk1 among isoenzymes. The derivatives 26a and 27a showed unprecedented selectivity and good growth inhibitory activity in cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Lina Ammar, Hung-Yu Lin, Shou-Ping Shih, Tsen-Ni Tsai, Yu-Ting Syu, Mohammad Abdel-Halim, Tsong-Long Hwang, Ashraf H. Abadi
Summary: PDE5 inhibitors have anticancer effects and cGMP elevation plays a role in CRC. We synthesized 31 derivatives of 9-benzylaminoacridine and found 22 of them showed micromolar or sub-micromolar inhibition against PDE5. Compounds 11, 12, and 28 exhibited significant growth inhibition, superior Topo II inhibitory activity, low micromolar PDE5 inhibition, and affected cell cycle progression in HCT-116 CRC cells. These compounds have potential as effective therapeutic agents against cancer.
Article
Chemistry, Medicinal
Youssef Y. Helmi, Niklas Papenkordt, Georg Rennar, Florence Gbahou, Ahmed K. El-Hady, Nedjma Labani, Karin Schmidtkunz, Stefan Boettcher, Ralf Jockers, Mohammad Abdel-Halim, Manfred Jung, Darius P. Zlotos
Summary: Anticancer drug conjugates that merge melatonin with the HDAC inhibitor vorinostat have shown higher potency in inhibiting HDAC and suppressing cancer cell growth. The most effective inhibitors, 3e, 5c, and 7c, linked the hydroxamic acid group of vorinostat to melatonin through a hexamethylene spacer. These hybrid ligands also demonstrated strong growth inhibition on various cancer cell lines. Their anticancer actions are driven by HDAC inhibition rather than melatonin receptor activation.
ARCHIV DER PHARMAZIE
(2023)
Article
Biochemistry & Molecular Biology
Donia E. Hafez, Mariam Dubiel, Gabriella La Spada, Marco Catto, David Reiner-Link, Yu-Ting Syu, Mohammad Abdel-Halim, Tsong-Long Hwang, Holger Stark, Ashraf H. Abadi
Summary: Introduced a multi-targeted ligand for neurodegenerative diseases, such as Alzheimer's disease, which offers an improved therapeutic alternative compared to the traditional one-target, one-molecule approach. Certain compounds showed potential for multi-targeting by evaluating their interactions with AChE, BuChE, and MAO-B, suggesting their potential as lead structures for developing new multi-targeting anti-AD agents.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Reem K. Fathalla, Matthias Engel, Christian Ducho
Summary: 8-Anilinonaphthalene-1-sulfonic acid (ANS) is a fluorescent probe commonly used to detect conformational changes in proteins. This study discovered that ANS can inhibit the activity of various isoforms of MurA and identified a more potent ANS analog. These findings highlight the potential of targeting the ANS binding pocket for the development of antibiotics.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Multidisciplinary
Nermin S. S. Ahmed, Heba E. E. El-Nakib, Marian M. M. Ramsis, Nouran O. O. Albably, Jannette Wober, Jan J. J. Weigand, Kai Schwedtmann, Oliver Zierau, Ashraf H. H. Abadi
Summary: This study presents a new class of potent Tamoxifen (TAM) analogues with both anticancer and antiviral activity, without increasing the risk of uterine cancer.
Review
Chemistry, Medicinal
Ahmed K. Elhady, Dalia S. El-Gamil, Mohammad Abdel-Halim, Ashraf H. Abadi
Summary: This review provides an updated assessment of the crucial role played by phosphodiesterase 5 (PDE5) inhibitors in the nitric oxide/cGMP pathway and their potential in treating various diseases. It discusses the medicinal chemistry and drug discovery aspects of PDE5 inhibitors, as well as the breakthrough development of allosteric inhibitors. Furthermore, the concept of multi-targeted ligands in relation to PDE5 inhibitors is critically evaluated.
Article
Chemistry, Medicinal
Reem A. Wagdy, Nader S. Abutaleb, Reem K. Fathalla, Yehia Elgammal, Stefanie Weck, Rusha Pal, Patrick D. Fischer, Christian Ducho, Ashraf H. Abadi, Mohamed N. Seleem, Matthias Engel, Mohammad Abdel-Halim
Summary: The synthesis of novel compounds targeting the cytoplasmic steps of peptidoglycan synthesis as potential antibacterial agents was reported. Some of these compounds showed potent inhibition of MurA enzyme and exhibited antibacterial activity against Clostridioides difficile strains. The inhibition of MurA enzyme was found to be responsible for the observed effect on bacterial growth.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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)