Izidor Sosič

University of Ljubljana

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Stanislav Gobec

University of Ljubljana

Christian Steinebach

University of Bonn

Michael Gütschow

University of Bonn

Janko Kos

University of Ljubljana

Martina Gobec

University of Ljubljana

Matic Proj

University of Ljubljana

Damijan Knez

University of Ljubljana

Aleša Bricelj

University of Ljubljana

Ana Mitrović

University of Ljubljana

Samo Turk

BioMed X Institute

Cooperative Institutions

University of Ljubljana

115

National Institute of Chemistry

Centre National de la Recherche Scientifique

University of Bonn

Jožef Stefan Institute

GlaxoSmithKline (Spain)

GlaxoSmithKline (United Kingdom)

Jožef Stefan International Postgraduate School

Goethe University Frankfurt

Ghent University

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In Silico Design and Enantioselective Synthesis of Functionalized Monocyclic 3‐Amino‐1‐carboxymethyl‐β‐lactams as Inhibitors of Penicillin‐Binding Proteins of Resistant Bacteria

Chemistry - A European Journal (2018)

Lena Decuyper Sari Deketelaere Lore Vanparys Marko Jukič Izidor Sosič

As a complement to the renowned bicyclic β-lactam antibiotics, monocyclic analogues provide a breath of fresh air in the battle against resistant bacteria. In that framework, the present study discloses the in silico design and unprecedented ten-step synthesis of eleven nocardicin-like enantiomerically pure 2-{3-[2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-2-oxoazetidin-1-yl}acetic acids starting from serine as a readily accessible precursor. The capability of this novel class of monocyclic 3-amino-β-lactams to inhibit penicillin-binding proteins (PBPs) of various (resistant) bacteria was assessed, revealing the potential of α-benzylidenecarboxylates as interesting leads in the pursuit of novel PBP inhibitors. No deactivation by representative enzymes belonging to the four β-lactamase classes was observed, while weak inhibition of class C β-lactamase P99 was demonstrated.

Penicillin binding proteins

Lactam

10.1002/chem.201801868

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Citations (16)

Another structural correction for 1‐oxo‐1 H ‐phenalene‐2,3‐dicarbonitriles: Synthesis of a potent BCL‐2 inhibiting 7‐phenoxy derivative

Archiv der Pharmazie (2021)

Izidor Sosič Martina Gobec Christian Steinebach Martin Schlesinger Gerd Bendas

Aromatic scaffolds are an important part of biologically active compounds and molecular probes used to study biochemical pathways and the involved targeted proteins of interest. 1-Oxo-1H-phenalene-2,3-dicarbonitrile-based compounds have been described as inhibitors of the BCL-2 family of proteins, and this core structure represents numerous possibilities for modifications that could lead to improved inhibitory potencies. Many studies demonstrated intriguing characteristics of these compounds in terms of reactivity and, interestingly, some contradictory literature reports appeared about reaction outcomes to synthesize them. Here, we initially provide a condensed overview of transformations performed on the phenalene scaffold, followed by the resynthesis of a 6-phenoxy-substituted derivative. We show that the initial determination of this particular structure was wrong and provide two-dimensional nuclear magnetic resonance (NMR) evidence to assign the structure properly. When preparing new derivatives using the same synthetic route, we observed 6- and 7-substituted regioisomers. After confirming their structures by NMR experiments, the ability of these compounds to inhibit BCL-2 was evaluated. The most potent 1-oxo-1H-phenalene-2,3-dicarbonitrile derivatives inhibited BCL-2 in the nanomolar range and showed double-digit micromolar cytotoxicity against four different cancer cell lines.

Derivative (finance)

Structural isomer

Reactivity

Proton NMR

10.1002/ardp.202100151

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Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments

ChemBioChem (2020)

László Petri Péter Ábrányi‐Balogh Tı́mea Imre Gyula Pálfy András Perczel

Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Herein, we present a toolbox of fragments containing a 3,5-bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity, aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine-containing enzymes.

Reactivity

Chemical Biology

10.1002/cbic.202000700

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Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

Christian Steinebach Izidor Sosič Aleša Bricelj Arunima Murgai Luca Bischof

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide represent the most typical cereblon (CRBN) recruiters that are frequently utilized in proteolysis-targeting chimera (PROTAC) design. These CRBN binders, however, cause degradation of IMiD neosubstrates and are innately unstable as they undergo hydrolytic degradation under mild conditions. Here we present the systematic approach towards novel non-phthalimide CRBN binders that were obtained via the simultaneous optimization of their physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features. Our efforts led to the discovery of conformationally-locked benzamide-type derivatives that mimic the interactions of the natural CRBN degron, displayed improved chemical stability, and showed a favorable selectivity profile with respect to the recruitment of neosubstrates. The usefulness of the most potent ligands was demonstrated by their conversion into potent degraders of BRD4 and HDAC6 that displayed superiority compared to previously described benchmark PROTACs. We show that our diversified CRBN ligands offer opportunities to design chemically inert proximity-inducing compounds with reduced neomorphic E3 ligase activity of CRBN.

Cereblon

Benzamide

Degron

Pomalidomide

10.26434/chemrxiv-2023-zshqp

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Cathepsin B inhibitors: Further exploration of the nitroxoline core

Bioorganic & Medicinal Chemistry Letters (2018)

Izidor Sosič Ana Mitrović Hrvoje Ćurić Damijan Knez Helena Brodnik

Endopeptidase

Proteolysis

Cathepsin S

Cathepsin E

Cathepsin A

Cathepsin L1

Cathepsin C

10.1016/j.bmcl.2018.02.042

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Citations (28)

New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

PLoS ONE (2011)

Samo Turk Olivier Verlaine Thomas Gerards Matej Živec Jan Humljan

Background Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs β-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for β-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. Methodology/Principal Findings Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. Conclusions We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.

Penicillin binding proteins

10.1371/journal.pone.0019418

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Repurposing of 8‐Hydroxyquinoline‐Based Butyrylcholinesterase and Cathepsin B Ligands as Potent Nonpeptidic Deoxyribonuclease I Inhibitors

ChemMedChem (2022)

Mihajlo Gajić Damijan Knez Izidor Sosič Janez Mravljak A. Meden

A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC50 values below 35 μM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC50 values below 60 and 20 μM. Selected derivatives were screened for various co-target binding affinities at dopamine D2 and D3 , histamine H3 and H4 receptors and inhibition of 5-lipoxygenase. Compound 8 bound to the H3 receptor and is highlighted as the most promising multifunctional ligand with a favorable pharmacokinetic profile and one of the most potent non-peptide DNase I inhibitors. The present study demonstrates that 8-hydroxyquinoline is a structural fragment critical for DNase I inhibition in the presented series of compounds.

Butyrylcholinesterase

IC50

Cathepsin G

10.1002/cmdc.202100694

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Citations (7)

CCDC 1997101: Experimental Crystal Structure Determination

The Cambridge Structural Database (2020)

Tim Van de Walle Marina Briand Ana Mitrović Izidor Sosič Stanislav Gobec

10.5517/ccdc.csd.cc2514m0

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Targeting TAK1: Evolution of inhibitors, challenges, and future directions

Pharmacology & Therapeutics (2025)

Nika Strašek Benedik Matic Proj Christian Steinebach Matej Sova Izidor Sosič

The increasing incidence of inflammatory and malignant diseases signifies the need to develop first-in-class drugs with novel mechanisms of action. In this respect, the transforming growth factor (TGF)-β-activated kinase 1 (TAK1), an essential part of several signaling pathways, is considered relevant and promising. This manuscript provides a brief overview of the signal transduction orchestrated by TAK1 within these pathways, followed by an in-depth and thorough analysis of the chemical matter demonstrated to inhibit this kinase. Special attention is given to the selectivity profiling of inhibitors, as well as to the outcomes of their biological characterization. Because published TAK1 inhibitors differ significantly in their kinome selectivity, active-site binding, and biological activity, we hope that this review will allow a judicial estimation of their quality and usefulness for TAK1-addressing assays. Our thoughts on the perspectives and possible developments of the field are also provided to assist scientists who are involved in the design and development of TAK1-targeting modulators.

Kinome

10.1016/j.pharmthera.2025.108810

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Synthesis of aminoboronic acid derivatives: an update on recent advances

Organic Chemistry Frontiers (2019)

Andrej Šterman Izidor Sosič Stanislav Gobec Zdenko Časar

Aminoboronic acids and their derivatives are particularly useful as drugs, probes and synthons. Recent developments in their synthesis are highlighted.

10.1039/c9qo00626e

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Citations (51)