Article
Chemistry, Medicinal
Robert J. Cherney, Prakash Anjanappa, Kumaravel Selvakumar, Douglas G. Batt, Gregory D. Brown, Anne Rose, Ragini Vuppugalla, Jing Chen, Jian Pang, Songmei Xu, Melissa Yarde, Andrew J. Tebben, Venkatram Reddy Paidi, Mary Ellen Cvijic, Arvind Mathur, Joel C. Barrish, Sandhya Mandlekar, Qihong Zhao, Percy H. Carter
Summary: Compound 3, identified as a potent and selective CCR2/5 dual antagonist, demonstrated excellent permeability and stability in vitro, as well as promising pharmacokinetic properties in animal studies, ultimately leading to its selection as a clinical candidate.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Immunology
Haixia Zhang, Ke Yang, Feng Chen, Qianqian Liu, Jingyu Ni, Weilong Cao, Yunqing Hua, Feng He, Zhihao Liu, Lan Li, Guanwei Fan
Summary: This article describes the mechanisms of action of the CCL2-CCR2 axis in cardiovascular diseases and explores its potential as a targeted therapy.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Immunology
Shaoping She, Liying Ren, Pu Chen, Mingyang Wang, Dongbo Chen, Ying Wang, Hongsong Chen
Summary: Chemokines are crucial for immune cell migration and positioning within tissues. CCR2 plays a significant role in liver pathology by recruiting immune cells to inflammation and tumor sites. This comprehensive review aims to provide insights into the roles of known chemokine ligands of CCR2 in liver diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Immunology
Patrick Grudzien, Henry Neufeld, Mbasogo Ebe Eyenga, Vadim Gaponenko
Summary: Chemokine G-protein coupled receptors are important drug targets for various diseases, but the development of chemokine receptor antagonists has been slow due to antagonist tolerance. The mechanisms underlying antagonist tolerance are poorly understood. This review provides a summary of the progress and challenges in therapeutic development of chemokine receptor antagonists, discusses the current knowledge of antagonist tolerance, and proposes new avenues for future investigation of this phenomenon. Additionally, it highlights the potential of modern methodologies in revealing novel mechanisms and advancing the development of tolerance-free antagonists.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Dentistry, Oral Surgery & Medicine
Shasha Yuan, Yiping Wei, Wenting Jiang, Fei Sun, Siqi Li, Qingqing Li, Zhanming Song, Zhongtian Liu, Yaqian Mo, Xuekang Wang, Ning Li, Ping Lv, Shaoping She, Cui Wang, Yu Zhang, Ying Wang, Wenjie Hu
Summary: CCR2 plays an important role in the development and progression of periodontitis. Cenicriviroc (CVC) shows potential as a drug for the prevention and treatment of periodontitis.
JOURNAL OF CLINICAL PERIODONTOLOGY
(2023)
Article
Immunology
Gregory P. Takacs, Christian J. Kreiger, Defang Luo, Guimei Tian, Julia S. Garcia, Loic P. Deleyrolle, Duane A. Mitchell, Jeffrey K. Harrison
Summary: Glioblastoma (GBM) is a highly malignant brain tumor with poor survival rates. The tumor microenvironment (TME) of GBM is characterized by immunosuppressive cells, including CCR2(+)/CX3CR1(+) myeloid-derived suppressor cells (MDSCs). These MDSCs are recruited to the TME through the chemokines CCL2 and CCL7. Targeting CCL2 and CCL7 may be a promising strategy for GBM treatment.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Hematology
Luka Zivkovic, Yaw Asare, Jurgen Bernhagen, Martin Dichgans, Marios K. Georgakis
Summary: This study systematically reviewed and meta-analyzed studies on the use of CCL2/CCR2 blockade in atheroprone mice. The results showed that CCL2/CCR2 blockade can attenuate atherosclerotic lesion size and improve lesion morphology. However, the majority of existing studies have major quality issues, highlighting the need for additional high-quality research.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Article
Chemistry, Medicinal
Adam Rolt, Daniel C. Talley, Seung Bum Park, Zongyi Hu, Andres Dulcey, Christopher Ma, Parker Irvin, Madeleine Leek, Amy Q. Wang, Andrew Stachulski, Xin Xu, Noel Southall, Marc Ferrer, T. Jake Liang, Juan J. Marugan
Summary: This study reveals the discovery and optimization of a 4-aminopiperidine (4AP) scaffold that targets the assembly stages of the HCV life cycle, showing synergistic effects with FDA-approved antiviral compounds and improved potency against HCV. Through structure-activity relationship studies, derivatives of the 4AP series with increased potency, reduced toxicity, and improved ADME properties have been identified.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Immunology
Michael Petermann, Zacharias Orfanos, Julie Sellau, Mohammad Gharaibeh, Hannelore Lotter, Bernhard Fleischer, Christian Keller
Summary: Our study investigated the role of CCR2 in a self-healing mouse model of O. tsutsugamushi infection, showing that CCR2 deficiency delayed disease onset, resolved symptoms, and resulted in higher concentrations of bacteria in the lung and impaired clearance. CCR2 drives blood monocytosis and the influx and activation of monocytes into the lung, accelerating bacterial replication and development of pulmonary inflammation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Medicine, Research & Experimental
Michael R. Ruff, Saadet Inan, Xiang Qun Shi, Joseph J. Meissler, Martin W. Adler, Toby K. Eisenstein, Ji Zhang
Summary: RAP-103, when co-administered with morphine, reduces the dose of morphine required for pain relief and the associated side effects. It also shows effectiveness as a non-opioid treatment for diabetic neuropathic pain.
Article
Biochemistry & Molecular Biology
Jing-Jing Zhang, Wanwan Zhang, Lei Zhang, Mengxuan Hu, Qi-Jie Xu, Yungen Xu
Summary: In this study, a series of novel 4-aminopiperidine derivatives were designed and synthesized as SMO/ERK dual inhibitors. These compounds showed strong inhibitory activities towards both SMO and ERK, and exhibited significant cytotoxicity against human cholangiocarcinoma cells.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Natalie E. Jasiewicz, Adam D. Brown, Michael Deci, Silvina Matysiak, H. Shelton Earp, Juliane Nguyen
Summary: In this study, an antibody-derived scFv that targets the second extracellular loop (ECL2) of CCR2 was identified using phage display. The blocking of ECL2 was found to inhibit macrophage migration and promote M1 inflammatory cytokine production as effectively as lipopolysaccharide (LPS).
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Virology
Alexandre P. Fernandes, Ana Agueda-Pinto, Ana Pinheiro, Hugo Rebelo, Pedro J. Esteves
Summary: The chemokine receptors CCR2 and CCR5 have undergone extensive gene conversion in multiple bat species. Bats are known to be reservoirs for viruses, and these results suggest that chimeric CCR2-CCR5 genes may provide a selective advantage against viruses that rely on these receptors.
Article
Fisheries
Frida Sommer, Natalia V. Ortiz Zacarias, Laura H. Heitman, Annemarie H. Meijer
Summary: The chemokine signaling axes CCR2-CCL2 and CXCR3-CXCL11 are potential targets for treating inflammatory disorders by recruiting leukocytes. In zebrafish larvae, inhibitors designed for humans have been shown to limit macrophage recruitment, suggesting the effectiveness of screening CCR2 inhibitors using this model.
DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY
(2021)
Article
Chemistry, Medicinal
Marco Daniele Parenti, Marina Naldi, Elisabetta Manoni, Edoardo Fabini, Daniela Cederfelt, Vladimir O. Talibov, Valeria Gressani, Ummu Guven, Valentina Grossi, Candida Fasano, Paola Sanese, Katia De Marco, Alexander A. Shtil, Alexander V. Kurkin, Andrea Altieri, U. Helena Danielson, Giuseppina Caretti, Cristiano Simone, Greta Varchi, Manuela Bartolini, Alberto Del Rio
Summary: Recent findings suggest that inhibiting SMYD3 methyltransferase could be a therapeutic strategy for certain deadly cancer types. This study designed active site-selective covalent SMYD3 inhibitors and demonstrated their ability to attenuate tumor biology at the cellular and genetic levels, inhibiting important genes and cell proliferation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Tamara A. M. Mocking, Hubert J. Sijben, Yime W. Vermeulen, Adriaan P. IJzerman, Laura H. Heitman
Summary: In this study, a label-free impedance-based transport assay was developed to detect OCT-mediated transport activity and inhibition. The method was effective in both OCT1-3 overexpressing cells and HeLa cells endogenously expressing OCT3, providing a valuable tool for studying drug-drug interactions and identifying potential inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
Summary: CCR2, a G protein-coupled receptor, is involved in various cancer-related processes. Mutations in CCR2 were investigated for their impact on receptor functionality and antagonist binding. Most mutants showed a decrease in G protein activation in response to the main ligand, while orthosteric antagonist binding was affected by specific mutations and allosteric antagonist binding was completely abolished in certain mutants. Considering CCR2 as a potential drug target in cancer, the negative effects of these mutations on receptor functionality and drug development should be considered.
BIOCHEMICAL PHARMACOLOGY
(2023)
Correction
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: In this study, a computational screening pipeline was developed to find new inhibitors for the NET protein. A data-driven approach was used to diversify the chemical space and select optimal proteins to model for NETs. A proteochemometric model was created and applied to an extensive compound database, resulting in the identification of five potential hit compounds with promising inhibitory potencies toward NET.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Xiaoting Li, Hao Chang, Jara Bouma, Laura V. de Paus, Partha Mukhopadhyay, Janos Paloczi, Mohammed Mustafa, Cas van der Horst, Sanjay Sunil Kumar, Lijie Wu, Yanan Yu, Richard J. B. H. N. van den Berg, Antonius P. A. Janssen, Aron Lichtman, Zhi-Jie Liu, Pal Pacher, Mario van der Stelt, Laura H. Heitman, Tian Hua
Summary: In this study, the authors report the discovery of a CB2R agonist, LEI-102, and investigate its selective activation of CB2R in conjunction with three other CBR ligands (APD371, HU308, and CP55,940). They identify key residues for CB2R activation and reveal the important role of lipophilicity in CB2R engagement. The favorable physico-chemical properties of LEI-102 enable its oral efficacy in a chemotherapy-induced nephropathy model.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Alena I. Siutkina, Svetlana Kalinina, Rongfang Liu, Laura H. Heitman, Anna Junker, Constantin G. Daniliuc, Dmitrii V. Kalinin
Summary: We report the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, which have a promising purinelike scaffold for drug discovery. The method is simple and fast, using easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived N,N'-disubstituted formamidines. Preliminary biological evaluation showed that the synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells with little to no influence on five tested purinergic receptors.
Article
Chemistry, Medicinal
Alessio Ciulli, Suzanne O'Connor, Chun-Wa Chung, Ingo V. Hartung, Andrea Testa, Danette L. Daniels, Laura H. Heitman
Summary: This report provides an overview of the 17th EFMC Short Course on Medicinal Chemistry, highlighting the inclusion of the exciting topic of Targeted Protein Degradation. It summarizes the successful event and key lectures, as well as the diverse representation of attendees from Europe, the US, and South Africa.
Article
Chemistry, Medicinal
Bert L. H. Beerkens, Inge M. Snijders, Joep Snoeck, Rongfang Liu, Anton T. J. Tool, Sylvia E. Le Devedec, Willem Jespers, Taco W. Kuijpers, Gerard J. P. van Westen, Laura H. Heitman, Adriaan P. IJzerman, Daan van der Es
Summary: This article describes the development of a new probe for detecting human A(3)AR, which has been validated through radioligand displacement, SDS-PAGE, confocal microscopy, and flow cytometry experiments. The probe is expected to be of great significance for future studies on the expression and function of A(3)AR in pathologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anna Vlachodimou, Jara Bouma, Michel De Cleyn, Didier Berthelot, Stefan Pype, Jean-Paul Bosmans, Herman van Vlijmen, Berthold Wroblowski, Laura H. Heitman, Adriaan P. IJzerman
Summary: Evaluation of kinetic parameters of drug-target binding, k(on), k(off), and residence time (RT), in addition to the traditional in vitro parameter of affinity is receiving increasing attention in the early stages of drug discovery. Target binding kinetics emerges as a meaningful concept for the evaluation of a ligand's duration of action and more generally drug efficacy and safety. We report the biological evaluation of a novel series of spirobenzo-oxazinepiperidinone derivatives as inhibitors of the human equilibrative nucleoside transporter 1 (hENT1, SLC29A1).
PURINERGIC SIGNALLING
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: This study developed a computational screening pipeline to identify new inhibitors for the high-affinity norepinephrine transporter (NET). By using the chemical space of related proteins, a data-driven approach was used to diversify the known chemical space for NET modeling. The final model, created through a two-step approach, predicted 46 chemically diverse candidates, of which five compounds showed promising inhibitory potency towards NET in experimental assays.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Bert L. H. Beerkens, Cagla Koc, Rongfang Liu, Bogdan I. Florea, Sylvia E. Le Devedec, Laura H. Heitman, Adriaan P. IJzerman, Daan Van Der Es
Summary: G protein-coupled receptors (GPCRs) have long been recognized as attractive drug targets, but many aspects of GPCR signaling remain poorly understood due to the difficulties encountered in studying them. In this study, we have developed an affinity-based probe for a prototype GPCR, the adenosine A(1) receptor (A(1)AR), and conducted various biochemical assays to evaluate its efficacy.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bert L. H. Beerkens, Xuesong Wang, Maria Avgeropoulou, Lisa N. Adistia, Jacobus P. D. van Veldhoven, Willem Jespers, Rongfang Liu, Laura H. Heitman, Adriaan P. IJzerman, Daan van der Es
Summary: This study investigates the role of signalling through the adenosine receptors in various pathological conditions and synthesizes potential covalent ligands for the A(2B)AR. The results show that a specific combination of variables is necessary for high affinity, irreversible binding and selectivity towards the A(2B)AR, with sulfonyl fluoride 24 (LUF7982) being a promising ligand.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Theresa Kissel, Changrong Ge, Lise Hafkenscheid, Joanneke C. Kwekkeboom, Linda M. Slot, Marco Cavallari, Yibo He, Karin A. van Schie, Rochelle D. Vergroesen, Arieke S. B. Kampstra, Sanne Reijm, Gerrie Stoeken-Rijsbergen, Carolien Koeleman, Lennard M. Voortman, Laura H. Heitman, Bingze Xu, Ger J. M. Pruijn, Manfred Wuhrer, Theo Rispens, Tom W. J. Huizinga, Hans Ulrich Scherer, Michael Reth, Rikard Holmdahl, Rene E. M. Toes
Summary: The presence of variable domain glycans (VDGs) in autoantibodies in rheumatoid arthritis affects B cell activation and binding, potentially contributing to the breach of tolerance in autoimmune diseases.
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
