Publications by authors named "Anna Koren"

7 Publications

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Green Hydrothermal Synthesis of Fluorescent 2,3-Diarylquinoxalines and Large-Scale Computational Comparison to Existing Alternatives.

ChemSusChem 2021 Apr 14;14(8):1780. Epub 2021 Apr 14.

Institute of Applied Synthetic Chemistry, Technische Universität Wien, Getreidemarkt 9/163, 1060, Vienna, Austria.

Invited for this month's cover is the group of Miriam Unterlass at the Technische Universität Wien and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. The image illustrates the synthesis of quinoxalines in "hot water" and the large-scale computational comparison of all existing syntheses of these quinoxalines. The Full Paper itself is available at 10.1002/cssc.202100433.
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http://dx.doi.org/10.1002/cssc.202100607DOI Listing
April 2021

Green Hydrothermal Synthesis of Fluorescent 2,3-Diarylquinoxalines and Large-Scale Computational Comparison to Existing Alternatives.

ChemSusChem 2021 Apr 26;14(8):1853-1863. Epub 2021 Mar 26.

Institute of Applied Synthetic Chemistry, Technische Universität Wien, Getreidemarkt 9/163, 1060, Vienna, Austria.

Here, the hydrothermal synthesis (HTS) of 2,3-diarylquinoxalines from 1,2-diketones and o-phenylendiamines (o-PDAs) was achieved. The synthesis is simple, fast, and generates high yields, without requiring any organic solvents, strong acids or toxic catalysts. Reaction times down to <10 min without decrease in yield could be achieved through adding acetic acid as promoter, even for highly apolar biquinoxalines (yield >90 % in all cases). Moreover, it was shown that HTS has high compatibility: (i) hydrochlorides, a standard commercial form of amines, could be used directly as combined amine source and acidic catalyst, and (ii) Boc-diprotected o-PDA could be directly employed as substrate that underwent HT deprotection. A systematic large-scale computational comparison of all reported syntheses of the presented quinoxalines from the same starting compounds showed that this method is more environmentally friendly and less toxic than all existing methods and revealed generic synthetic routes for improving reaction yields. Finally, the application of the synthesized compounds as fluorescent dyes for cell staining was explored.
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http://dx.doi.org/10.1002/cssc.202100433DOI Listing
April 2021

Acute BAF perturbation causes immediate changes in chromatin accessibility.

Nat Genet 2021 03 8;53(3):269-278. Epub 2021 Feb 8.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Cancer-associated, loss-of-function mutations in genes encoding subunits of the BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes often cause drastic chromatin accessibility changes, especially in important regulatory regions. However, it remains unknown how these changes are established over time (for example, immediate consequences or long-term adaptations), and whether they are causative for intracomplex synthetic lethalities, abrogating the formation or activity of BAF complexes. In the present study, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits, we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in an almost complete loss of chromatin accessibility at BAF-controlled sites, especially also at superenhancers, providing a mechanism for intracomplex synthetic lethalities.
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http://dx.doi.org/10.1038/s41588-021-00777-3DOI Listing
March 2021

Pooled protein tagging, cellular imaging, and in situ sequencing for monitoring drug action in real time.

Genome Res 2020 12 17;30(12):1846-1855. Epub 2020 Nov 17.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.

The levels and subcellular localizations of proteins regulate critical aspects of many cellular processes and can become targets of therapeutic intervention. However, high-throughput methods for the discovery of proteins that change localization either by shuttling between compartments, by binding larger complexes, or by localizing to distinct membraneless organelles are not available. Here we describe a scalable strategy to characterize effects on protein localizations and levels in response to different perturbations. We use CRISPR-Cas9-based intron tagging to generate cell pools expressing hundreds of GFP-fusion proteins from their endogenous promoters and monitor localization changes by time-lapse microscopy followed by clone identification using in situ sequencing. We show that this strategy can characterize cellular responses to drug treatment and thus identify nonclassical effects such as modulation of protein-protein interactions, condensate formation, and chemical degradation.
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http://dx.doi.org/10.1101/gr.261503.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706735PMC
December 2020

Rational discovery of molecular glue degraders via scalable chemical profiling.

Nat Chem Biol 2020 11 3;16(11):1199-1207. Epub 2020 Aug 3.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.
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http://dx.doi.org/10.1038/s41589-020-0594-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116640PMC
November 2020

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs.

Nat Chem Biol 2020 04 9;16(4):469-478. Epub 2020 Mar 9.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Solute carriers (SLCs) are the largest family of transmembrane transporters in humans and are major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR-Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the screened compounds suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.
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http://dx.doi.org/10.1038/s41589-020-0483-3DOI Listing
April 2020