New Inhibitors of β-1,4-Galactosyltransferase I Discovered by Virtual Screening.

Seven different enzymes comprise the galactosyltransferases family, of which β-1,4-galactosyltransferase I (β-1,4-GALT1) is the major contributor to galactosylation activity in cells. Since abnormalities in galactosylation are associated with many pathophysiological conditions, β-1,4-GALT1 is an interesting new target for drug discovery and molecular probe design. There are several known β-1,4-GALT1 inhibitors, but most of them suffer from low cell permeability and thus low in vivo activity.

Unveiling the antiglioblastoma potential of harmicens, harmine and ferrocene hybrids.

The poor prognosis of glioblastoma multiforme, inadequate treatment options, and growing drug resistance urge the need to find new effective agents. Due to the significant anti-cancer potential of harmicens, hybrid compounds which comprise harmine/β-carboline and ferrocene moiety, we investigated their antiglioblastoma potential and mechanism of action (inhibition of DYRK1A, Hsp90, anti-oxidative activity). The results have shown that triazole-type harmicens, namely , with a ferrocene moiety in C-3 position of the β-carboline ring ( = 3.

First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo.

Heat shock protein 90 (Hsp90) and topoisomerase IIα (TopoIIα) are members of the GHKL protein superfamily, both with clinically validated roles as anticancer drug targets. We report the discovery of the first class of dual inhibitors targeting the ATP-binding site of TopoIIα and the C-terminal domain of Hsp90, displaying potent cancer growth inhibition both in vitro and in vivo. Initially, a known TopoIIα inhibitor, compound 3, was shown to bind to the C-terminal domain of Hsp90, but not to its ATP-binding N-terminal domain.

Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders.

Due to their impact on several oncogenic client proteins, the Hsp90 family of chaperones has been widely studied for the development of potential anticancer agents. Although several Hsp90 inhibitors have entered clinical trials, most were unsuccessful because they induced a heat shock response (HSR). This issue can be circumvented by using isoform-selective inhibitors, but the high similarity in the ATP-binding sites between the isoforms presents a challenge.

New -phenylpyrrolamide inhibitors of DNA gyrase with improved antibacterial activity.

This study presents the discovery of a new series of -phenylpyrrolamide inhibitors of bacterial DNA gyrase with improved antibacterial activity. The most potent inhibitors had low nanomolar IC values against DNA gyrase (IC; 2-20 nM) and topoisomerase IV (22i, IC = 143 nM). Importantly, none of the compounds showed activity against human DNA topoisomerase IIα, indicating selectivity for bacterial targets.

Discovery of new Hsp90-Cdc37 protein-protein interaction inhibitors: screening and optimization of anticancer activity.

The interaction between heat shock protein 90 (Hsp90) and Hsp90 co-chaperone cell-division cycle 37 (Cdc37) is crucial for the folding and maturation of several oncogenic proteins, particularly protein kinases. This makes the inhibition of this protein-protein interaction (PPI) an interesting target for developing new anticancer compounds. However, due to the large interaction surface, developing PPI inhibitors is challenging.

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains.

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes.

Targeting -Acetylglucosaminidase in with Iminosugar Inhibitors.

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant , which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance.

Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double π-Stack in a Unique Pocket.

Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological purposes. Structure-guided design led to the discovery of potent and selective glycomimetic-heterocycle hybrid ligands, with a 4-(-bromophenyl)phthalazinone derivative displaying a 34 μM for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C.

New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor .

Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E.

Exploration and optimisation of structure-activity relationships of new triazole-based C-terminal Hsp90 inhibitors towards in vivo anticancer potency.

The development of new anticancer agents is one of the most urgent topics in drug discovery. Inhibition of molecular chaperone Hsp90 stands out as an approach that affects various oncogenic proteins in different types of cancer. These proteins rely on Hsp90 to obtain their functional structure, and thus Hsp90 is indirectly involved in the pathophysiology of cancer.

Identification of a Novel Structural Class of H1 Inhibitors by Structure-Based Virtual Screening.

The human voltage-gated proton channel, hH1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of H1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hH1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human H1 channel.

Discovery of two non-UDP-mimic inhibitors of O-GlcNAc transferase by screening a DNA-encoded library.

Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic the main interactions of glycosyl donor UDP-GlcNAc with the enzyme. Until recently, screening of DNA-encoded libraries for discovering hits against protein targets was dedicated to a few laboratories around the world, but has become accessible to wider public with the recent launch of the DELopen platform.

Benzothiazole DNA gyrase inhibitors and their conjugates with siderophore mimics: design, synthesis and evaluation.

Benzothiazole-based bacterial DNA gyrase and topoisomerase IV inhibitors are promising new antibacterial agents with potent activity against Gram-positive and Gram-negative bacterial strains. The aim of this study was to improve the uptake of these inhibitors into the cytoplasm of Gram-negative bacteria by conjugating them to the small siderophore mimics. The best conjugate 18b displayed potent DNA gyrase and topoisomerase IV inhibition.

Virtual Screening Assisted Search for Inhibitors of the Translocated Intimin Receptor of Enteropathogenic Escherichia Coli.

This study aimed to identify inhibitors of the translocated intimin receptor (Tir) of enteropathogenic Escherichia coli (EPEC). EPEC is an intestinal pathogen that causes diarrhea and is a major health concern worldwide. Because Tir is a key virulence factor involved in EPEC pathogenesis, inhibiting its function is a potential strategy for controlling EPEC infections.

Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens.

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor , in complex with GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound showed low nanomolar inhibition of DNA gyrase (IC < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.

Immunosuppressive effects of new thiophene-based K1.3 inhibitors.

Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca homeostasis. Here, we present the structure-activity relationship, K1.

New aryl and acylsulfonamides as state-dependent inhibitors of Na1.3 voltage-gated sodium channel.

Voltage-gated sodium channels (Nas) play an essential role in neurotransmission, and their dysfunction is often a cause of various neurological disorders. The Na1.3 isoform is found in the CNS and upregulated after injury in the periphery, but its role in human physiology has not yet been fully elucidated.

Correction: Gubič et al. Design of New Potent and Selective Thiophene-Based K1.3 Inhibitors and Their Potential for Anticancer Activity. 2022, , 2595.

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Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities.

The heat shock protein 90 (Hsp90) family consists of four highly conserved isoforms: the mitochondrial TRAP-1, the endoplasmic reticulum-localised Grp94, and the cytoplasmic Hsp90α and Hsp90β. Since the late 1990s, this family has been extensively studied as a potential target for the treatment of cancer, neurological disorders, and infectious diseases. The initial approach was to develop non-selective, so-called pan-Hsp90 ATP-competitive inhibitors of the N-terminal domain.