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JOURNAL ARTICLE
Yong Yan, Hanwen Liu, Di Wu, Zhihao Gu, Wenhao Guo, Hequan Yao, Kejiang Lin, Xuanyi Li
Background: The epidemic caused by SARS-CoV-2 swept the world in 2019. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in viral replication, and its inhibition could inhibit viral replication. Materials & methods: The virtual screen based on receptor-ligand pharmacophore models and molecular docking were conducted to obtain the novel scaffolds of the 3CLpro. The molecular dynamics simulation was also carried out. All compounds were synthesized and evaluated in biochemical assays. Results: The compound C2 could inhibit 3CLpro with a 72% inhibitory rate at 10 μM...
April 15, 2024: Future Medicinal Chemistry
#42
JOURNAL ARTICLE
Weida Liang, Aaron D Krabill, Katelyn S Gallagher, Christine Muli, Zihan Qu, Darci Trader, Zhong-Yin Zhang, Mingji Dai
Natural products have been playing indispensable roles in the development of lifesaving drug molecules. They are also valuable sources for covalent protein modifiers. However, they often are scarce in nature and have complex chemical structures, which are limiting their further biomedical development. Thus, natural product-inspired small molecules which still contain the essence of the parent natural products but are readily available and amenable for structural modification, are important and desirable in searching for lead compounds for various disease treatment...
April 28, 2024: Tetrahedron
#43
JOURNAL ARTICLE
Xiao Yan, Chuanhua Qu, Qin Li, Lei Zhu, Henry H Y Tong, Huanxiang Liu, Qin Ouyang, Xiaojun Yao
Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation...
December 2024: Computational and Structural Biotechnology Journal
#44
REVIEW
Andrea Visentin, Sara Frazzetto, Livio Trentin, Annalisa Chiarenza
In the last few years, several agents targeting molecules that sustain the survival and the proliferation of chronic lymphocytic leukemia (CLL) cells have become clinically available. Most of these drugs target surface proteins, such as CD19 or CD20, via monoclonal or bispecific monoclonal antibodies (BsAbs), CAR T cells, intracellular proteins like BTK by using covalent or non-covalent inhibitors or BCL2 with first or second generation BH3-mimetics. Since the management of CLL is evolving quickly, in this review we highlighted the most important innovative treatments including novel double and triple combination therapies, CAR T cells and BsAbs for CLL...
March 26, 2024: Cancers
#45
JOURNAL ARTICLE
Moritz Schwarz, Maksym Kurkunov, Florian Wittlinger, Ramona Rudalska, Guiqun Wang, Martin Peter Schwalm, Alexander Rasch, Benedikt Wagner, Stefan A Laufer, Stefan Knapp, Daniel Dauch, Matthias Gehringer
Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SN Ar) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity...
April 11, 2024: Journal of Medicinal Chemistry
#46
JOURNAL ARTICLE
Ali Camara, Heerak Chugh, Alyssa George, Lukas Dolidze, Kevin Ryu, Katrina J Holly, Daniel P Flaherty, Seema Mattoo
AMPylation-the covalent transfer of an AMP from ATP onto a target protein-is catalyzed by the human enzyme HYPE/FicD to regulate its substrate, the heat shock chaperone BiP. HYPE-mediated AMPylation of BiP is critical for maintaining proteostasis in the ER (endoplasmic reticulum) and mounting an UPR (unfolded protein response) in times of proteostatic imbalance. Thus, manipulating HYPE's enzymatic activity is a key therapeutic strategy towards the treatment of various protein misfolding diseases, including neuropathy and early onset diabetes associated with two recently identified clinical mutations of HYPE...
April 8, 2024: Cell Stress & Chaperones
#47
JOURNAL ARTICLE
Daniel T Hansen, Nicole J Rueb, Nathan D Levinzon, Thomas E Cheatham, Robert Gaston, Kh Tanvir Ahmed, Sandra Osburn-Staker, James E Cox, Gregory B Dudley, Amy M Barrios
Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid...
April 8, 2024: Bioorganic & Medicinal Chemistry Letters
#48
JOURNAL ARTICLE
Jessica Guerra, Mirella Belleri, Giulia Paiardi, Chiara Tobia, Davide Capoferri, Marzia Corli, Elisa Scalvini, Marco Ghirimoldi, Marcello Manfredi, Rebecca C Wade, Marco Presta, Luca Mignani
Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients and Galc -deficient twitcher mice (an authentic animal model of the disease) indicate that the pathogenesis of this disorder is the consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine), ignoring the possibility that this enzyme may exert a wider biological impact...
December 2024: Computational and Structural Biotechnology Journal
#49
JOURNAL ARTICLE
Lijing Zhang, Xuping Xie, Hannan Luo, Runtong Qian, Yang Yang, Hongtao Yu, Jing Huang, Pei-Yong Shi, Qi Hu
Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates...
April 9, 2024: Cell Discovery
#50
JOURNAL ARTICLE
Christoph A Schatz, Sabine Zitzmann-Kolbe, Ingrid Moen, Monika Klotz, Shankari Nair, Stefan Stargard, Roger M Bjerke, Katrine Wickstrøm Biseth, Yuan Zeng Feng, Bård Indrevoll, Véronique Cruciani, Jenny Karlsson, Bernard Haendler, Carsten H Nielsen, Maria Z Alfsen, Stefanie Hammer, Hartwig Hennekes, Alan Cuthbertson, Urs B Hagemann, Aasmund Larsen
PURPOSE: Initially, prostate cancer responds to hormone therapy but eventually resistance develops. Beta emitter-based PSMA (prostate-specific membrane antigen)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs...
April 9, 2024: Clinical Cancer Research
#51
REVIEW
Kosmas Alexandros Pervanidis, Giovanni Danilo D'Angelo, Jörn Weisner, Sven Brandherm, Daniel Rauh
Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective...
April 9, 2024: Journal of Medicinal Chemistry
#52
JOURNAL ARTICLE
Jure Stojan, Alessandro Pesaresi, Anže Meden, Doriano Lamba
Chemical warfare nerve agents and pesticides, known as organophosphorus compounds inactivate cholinesterases (ChEs) by phosphorylating the serine hydroxyl group located at the active site of ChEs. Over the course of time, phosphorylation is followed by loss of an organophosphate-leaving group and the bond with ChEs becomes irreversible, a process known as aging. Differently, structurally related irreversible catalytic poisons bearing sulfur instead of phosphorus convert ChEs in its aged form only by covalently binding to the key catalytic serine...
May 2024: Protein Science
#53
REVIEW
Fateeha Furqan, Nirav N Shah
Despite significantly improving outcomes in patients with B-cell malignancies, covalent Bruton tyrosine kinase (BTK) inhibitors are limited by toxicities and the development of resistance. Some toxicities can be life-threatening, such as cardiotoxicity. These toxicities result from off-target effects of covalent BTK inhibitors and frequently lead to dose reductions and discontinuations of the drug. Noncovalent BTK inhibitors bind BTK in a unique fashion and, to date, have demonstrated an excellent safety profile as well as efficacy against a variety of B-cell malignancies...
April 2024: Clinical Advances in Hematology & Oncology: H&O
#54
JOURNAL ARTICLE
Gabriele Picco, Yanhua Rao, Angham Al Saedi, Yang Lee, Sara F Vieira, Shriram Bhosle, Kieron May, Carmen Herranz-Ors, Samantha J Walker, Raynold Shenje, Cansu Dincer, Freddy Gibson, Ruby Banerjee, Zoe Hewitson, Thilo Werner, Joshua E Cottom, Yang Peng, Nanhua Deng, Philip Landis, Daniela Conticelli, Katrina McCarten, Jacob Bush, Mamta Sharma, Howard Lightfoot, David House, Emma Milford, Emma K Grant, Michal P Glogowski, Craig D Wagner, Marcus Bantscheff, Anna Rutkowska-Klute, Cell Model Network Uk Group, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, H Christian Eberl, Brian T Jones, Jessica L Schneck, Dennis J Murphy, Emile E Voest, Joshua P Taygerly, Michael P DeMartino, Matthew A Coelho, Jonathan Houseley, Geeta Sharma, Benjamin J Schwartz, Mathew J Garnett
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage...
April 9, 2024: Cancer Discovery
#55
JOURNAL ARTICLE
Huiting Hu, Yuqian Cai, Yuanfang Shi, Shengyu Zhang, Xiaoxuan Yu, Tonghui Ma, Shanting Liao
The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been approved by the Food and Drug Administration (FDA) of the United States. In our current study, we showed that dimethyl fumarate (DMF) efficiently suppressed the activation of the NLRP3 inflammasome induced by multiple agonists and covalently modified Cys673 of NLRP3, thereby impeding the interaction between NLRP3 and NEK7. The inhibitory effect of DMF was nullified by anaplerosis of the Cys673 mutant (but not the wild-type) NLRP3 in Nlrp3 -/- THP-1 cells...
April 19, 2024: IScience
#56
JOURNAL ARTICLE
Lifang Wang, Yaowen Liang, Pan Luo, Manna Huang, Yiqian Wan
Discovering novel NDM-1 inhibitors is an urgent task for treatment of 'superbug' infectious diseases. In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure-activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1...
April 3, 2024: Bioorganic Chemistry
#57
JOURNAL ARTICLE
Saan Voss, Jörg Rademann, Christoph Nitsche
Flaviviruses can cause severe illness in humans. Effective and safe vaccines are available for some species; however, for many flaviviruses disease prevention or specific treatments remain unavailable. The viral replication cycle depends on the proteolytic activity of the NS2B-NS3 protease, which releases functional viral proteins from a non-functional polyprotein precursor, rendering the protease a promising drug target. In this study, we characterised recombinant NS2B-NS3 proteases from ten flaviviruses including three unreported proteases from the Usutu, Kyasanur forest disease and Powassan viruses...
April 4, 2024: Antiviral Research
#58
JOURNAL ARTICLE
Alexandria M Chan, Ashley Mitchell, Lena Grogan, Paul Shapiro, Steven Fletcher
Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity...
March 16, 2024: Bioorganic & Medicinal Chemistry
#59
JOURNAL ARTICLE
Xin-Yu Cao, Xinge Li, Feng Wang, Yichen Duan, Xingmei Wu, Guo-Qiang Lin, Meiyu Geng, Min Huang, Ping Tian, Shuai Tang, Dingding Gao
The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC50 = 1.98 ± 0.66 µM). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC50 = 0...
April 3, 2024: Bioorganic Chemistry
#60
JOURNAL ARTICLE
Vindhya Nawaratne, Anya K Sondhi, Omar Abdel-Wahab, Justin Taylor
Bruton's tyrosine kinase (BTK) is central to the survival of malignant and normal B-lymphocytes and has been a crucial therapeutic target of several generations of kinase inhibitors and newly developed degraders. These new means for targeting BTK have added additional agents to the armamentarium for battling cancers dependent on B-cell receptor (BCR) signaling, including chronic lymphocytic leukemia and other non-Hodgkin lymphomas. However, the development of acquired resistance mutations to each of these classes of BTK inhibitors has led to new challenges in targeting BTK as well as novel insights into BCR signaling...
April 5, 2024: Clinical Cancer Research
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