Publications by authors named "Herbert Waldmann"

392 Publications

Natural product fragment combination to performance-diverse pseudo-natural products.

Nat Commun 2021 03 25;12(1):1883. Epub 2021 Mar 25.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
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http://dx.doi.org/10.1038/s41467-021-22174-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994817PMC
March 2021

Morphological profiling of small molecules.

Cell Chem Biol 2021 Mar;28(3):300-319

Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany. Electronic address:

Profiling approaches such as gene expression or proteome profiling generate small-molecule bioactivity profiles that describe a perturbed cellular state in a rather unbiased manner and have become indispensable tools in the evaluation of bioactive small molecules. Automated imaging and image analysis can record morphological alterations that are induced by small molecules through the detection of hundreds of morphological features in high-throughput experiments. Thus, morphological profiling has gained growing attention in academia and the pharmaceutical industry as it enables detection of bioactivity in compound collections in a broader biological context in the early stages of compound development and the drug-discovery process. Profiling may be used successfully to predict mode of action or targets of unexplored compounds and to uncover unanticipated activity for already characterized small molecules. Here, we review the reported approaches to morphological profiling and the kind of bioactivity that can be detected so far and, thus, predicted.
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http://dx.doi.org/10.1016/j.chembiol.2021.02.012DOI Listing
March 2021

Thermal proteome profiling identifies the membrane-bound purinergic receptor P2X4 as a target of the autophagy inhibitor indophagolin.

Cell Chem Biol 2021 Mar 9. Epub 2021 Mar 9.

Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Technische Universität Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Straße 6, 44227 Dortmund, Germany. Electronic address:

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery of small molecules targeting these receptors may yield insights into their biology. However, due to their intrinsic properties, membrane protein targets often cannot be identified by means of established approaches, in particular affinity-based proteomics, calling for the exploration of new methods. Here, we report the identification of indophagolin as representative member of an indoline-based class of autophagy inhibitors through a target-agnostic phenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified the purinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolin targets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable the de novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.
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http://dx.doi.org/10.1016/j.chembiol.2021.02.017DOI Listing
March 2021

Pseudo Natural Products-Chemical Evolution of Natural Product Structure.

Angew Chem Int Ed Engl 2021 Mar 1. Epub 2021 Mar 1.

Max-Planck Institute of Molecular Physiology, Otto-Hahn Strasse 11, 44227, Dortmund, Germany.

Pseudo-natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non-biogenic fusions of NP-derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human-driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.
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http://dx.doi.org/10.1002/anie.202016575DOI Listing
March 2021

Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5-MEP50 Complex.

Chembiochem 2021 Feb 24. Epub 2021 Feb 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The PRMT5-MEP50 methyltransferase complex plays a key role in various cancers and is regulated by different protein-protein interactions. Several proteins have been reported to act as adaptor proteins that recruit substrate proteins to the active site of PRMT5 for the methylation of arginine residues. To define the interaction between these adaptor proteins and PRMT5, we employed peptide truncation and mutation studies and prepared truncated protein constructs. We report the characterisation of the interface between the TIM barrel of PRMT5 and the adaptor proteins pICln, RioK1 and COPR5, and identify the consensus amino acid sequence GQF[D/E]DA[E/D] involved in binding. Protein crystallography revealed that the RioK1 derived peptide interacts with a novel PPI site.
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http://dx.doi.org/10.1002/cbic.202100079DOI Listing
February 2021

Discovery of a σ receptor antagonist by combination of unbiased cell painting and thermal proteome profiling.

Cell Chem Biol 2021 Jan 21. Epub 2021 Jan 21.

Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany; TU Dortmund University, Emil-Figge-Str. 72, 44221 Dortmund, Germany. Electronic address:

Phenotypic screening for bioactive small molecules is typically combined with affinity-based chemical proteomics to uncover the respective molecular targets. However, such assays and the explored bioactivity are biased toward the monitored phenotype, and target identification often requires chemical derivatization of the hit compound. In contrast, unbiased cellular profiling approaches record hundreds of parameters upon compound perturbation to map bioactivity in a broader biological context and may link a profile to the molecular target or mode of action. Herein we report the discovery of the diaminopyrimidine DP68 as a Sigma 1 (σ) receptor antagonist by combining morphological profiling using the Cell Painting assay and thermal proteome profiling. Our results highlight that integration of complementary profiling approaches may enable both detection of bioactivity and target identification for small molecules.
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http://dx.doi.org/10.1016/j.chembiol.2021.01.009DOI Listing
January 2021

Cell-Based Identification of New IDO1 Modulator Chemotypes.

Angew Chem Int Ed Engl 2021 Apr 24;60(18):9869-9874. Epub 2021 Mar 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227, Dortmund, Germany.

The immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO1) strengthens cancer immune escape, and inhibition of IDO1 by means of new chemotypes and mechanisms of action is considered a promising opportunity for IDO1 inhibitor discovery. IDO1 is a cofactor-binding, redox-sensitive protein, which calls for monitoring of IDO1 activity in its native cellular environment. We developed a new, robust fluorescence-based assay amenable to high throughput, which detects kynurenine in cells. Screening of a ca. 150 000-member compound library discovered unprecedented, potent IDO1 modulators with different mechanisms of action, including direct IDO1 inhibitors, regulators of IDO1 expression, and inhibitors of heme synthesis. Three IDO1-modulator chemotypes were identified that bind to apo-IDO1 and compete with the heme cofactor. Our new cell-based technology opens up novel opportunities for medicinal chemistry programs in immuno-oncology.
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http://dx.doi.org/10.1002/anie.202016004DOI Listing
April 2021

Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products.

Angew Chem Int Ed Engl 2021 02 12;60(9):4648-4656. Epub 2021 Jan 12.

Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo-NPs, NP-derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155-member pyrroquinoline pseudo-NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological "cell painting" assay followed by principal component analysis revealed that the pseudo-NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
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http://dx.doi.org/10.1002/anie.202013731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986669PMC
February 2021

Enantioselective Synthesis of Five-Membered-Ring Atropisomers with a Chiral Rh(III) Complex.

Org Lett 2020 12 13;22(23):9199-9202. Epub 2020 Nov 13.

Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany.

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C-H functionalization method using our chiral RhCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.
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http://dx.doi.org/10.1021/acs.orglett.0c03355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735750PMC
December 2020

A protein tertiary structure mimetic modulator of the Hippo signalling pathway.

Nat Commun 2020 10 27;11(1):5425. Epub 2020 Oct 27.

Max Planck Institute for Molecular Physiology, Dortmund, Germany.

Transcription factors are key protein effectors in the regulation of gene transcription, and in many cases their activity is regulated via a complex network of protein-protein interactions (PPI). The chemical modulation of transcription factor activity is a long-standing goal in drug discovery but hampered by the difficulties associated with the targeting of PPIs, in particular when extended and flat protein interfaces are involved. Peptidomimetics have been applied to inhibit PPIs, however with variable success, as for certain interfaces the mimicry of a single secondary structure element is insufficient to obtain high binding affinities. Here, we describe the design and characterization of a stabilized protein tertiary structure that acts as an inhibitor of the interaction between the transcription factor TEAD and its co-repressor VGL4, both playing a central role in the Hippo signalling pathway. Modification of the inhibitor with a cell-penetrating entity yielded a cell-permeable proteomimetic that activates cell proliferation via regulation of the Hippo pathway, highlighting the potential of protein tertiary structure mimetics as an emerging class of PPI modulators.
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http://dx.doi.org/10.1038/s41467-020-19224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591920PMC
October 2020

Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48.

Angew Chem Int Ed Engl 2021 01 24;60(4):1813-1820. Epub 2020 Nov 24.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.
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http://dx.doi.org/10.1002/anie.202009749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894522PMC
January 2021

Guided by evolution: from biology oriented synthesis to pseudo natural products.

Nat Prod Rep 2020 11;37(11):1497-1510

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany. and Faculty of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.

Covering: up to 2020 Natural products (NPs) provide inspiration for the design of biologically active compounds and libraries. In this review, we cover several experimental and in silico approaches, which have been used to simplify NPs and guide NP-based library design. Earlier approaches, like the structural classification of natural products (SCONP) and biology-oriented synthesis (BIOS), focus on the identification of activity determining scaffolds and the synthesis of corresponding compound collections. More recently, NP fragments identified by means of cheminformatic analysis of the Dictionary of Natural Products (DNP) have been combined in unprecedented fashions to yield pseudo natural products (pseudo NPs), which show biological activities unrelated to the guiding NPs. Each approach was also the source of chemical innovation, in which synthetic methods were established for the rapid assembly of NP-inspired compounds and libraries.
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http://dx.doi.org/10.1039/d0np00015aDOI Listing
November 2020

Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket.

J Med Chem 2020 10 1;63(20):11972-11989. Epub 2020 Oct 1.

Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Straße 11, 44227 Dortmund, Germany.

Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, such as organogenesis and cell growth, and elevated TEAD activity is associated with tumorigenesis. Hence, novel modulators of TEAD and methods for their identification are in high demand. We describe the development of a new "thiol conjugation assay" for identification of novel small molecules that bind to the TEAD central pocket. The assay monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket by small molecules. Screening of a collection of compounds revealed kojic acid analogues as TEAD inhibitors, which covalently target the cysteine in the central pocket, block the interaction with coactivator yes-associated protein with nanomolar apparent IC values, and reduce TEAD target gene expression. This methodology promises to enable new medicinal chemistry programs aimed at the modulation of TEAD activity.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586386PMC
October 2020

Discovery of small-molecule modulator of heterotrimeric G-protein by integrated phenotypic profiling and chemical proteomics.

Biosci Biotechnol Biochem 2020 Dec 31;84(12):2484-2490. Epub 2020 Aug 31.

RIKEN-Max Planck Joint Research Division for Systems Chemical Biology, RIKEN Center for Sustainable Resource Science , Saitama, Japan.

Discovery of small-molecule inducers of unique phenotypic changes combined with subsequent target identification often provides new insights into cellular functions. Here, we applied integrated profiling based on cellular morphological and proteomic changes to compound screening. We identified an indane derivative, NPD9055, which is mechanistically distinct from reference compounds with known modes of action. Employing a chemical proteomics approach, we then showed that NPD9055 binds subunits of heterotrimeric G-protein G. An [S]GTPγS-binding assay revealed that NPD9055 inhibited GDP/GTP exchange on a Gα subunit induced by a G-protein-coupled receptor agonist, but not on another G-protein from the Gα family. In intact HeLa cells, NPD9055 induced an increase in intracellular Ca levels and ERK/MAPK phosphorylation, both of which are regulated by Gβγ, following its dissociation from Gα. Our observations suggest that NPD9055 targets Gα and thus regulates Gβγ-dependent cellular processes, most likely by causing the dissociation of Gβγ from Gα.
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http://dx.doi.org/10.1080/09168451.2020.1812375DOI Listing
December 2020

Morphological Profiling Identifies a Common Mode of Action for Small Molecules with Different Targets.

Chembiochem 2020 Nov 24;21(22):3197-3207. Epub 2020 Jul 24.

Max-Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, 44227, Germany.

Unbiased morphological profiling of bioactivity, for example, in the cell painting assay (CPA), enables the identification of a small molecule's mode of action based on its similarity to the bioactivity of reference compounds, irrespective of the biological target or chemical similarity. This is particularly important for small molecules with nonprotein targets as these are rather difficult to identify with widely employed target-identification methods. We employed morphological profiling using the CPA to identify compounds that are biosimilar to the iron chelator deferoxamine. Structurally different compounds with different annotated cellular targets provoked a shared physiological response, thereby defining a cluster based on their morphological fingerprints. This cluster is based on a shared mode of action and not on a shared target, that is, cell-cycle modulation in the S or G2 phase. Hierarchical clustering of morphological fingerprints revealed subclusters that are based on the mechanism of action and could be used to predict target-related bioactivity.
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http://dx.doi.org/10.1002/cbic.202000381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754162PMC
November 2020

Rh -Catalyzed C-H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones.

Chemistry 2020 Aug 21;26(47):10729-10734. Epub 2020 Jul 21.

Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

Rh -catalyzed C-H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.
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http://dx.doi.org/10.1002/chem.202002384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496876PMC
August 2020

Development of Glucose Transporter (GLUT) Inhibitors.

European J Org Chem 2020 May 28;2020(16):2321-2329. Epub 2019 Nov 28.

Department of Chemical Biology Max Planck Institute of Molecular Physiology Otto-Hahn-Str. 11 44227 Dortmund Germany.

The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction.
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http://dx.doi.org/10.1002/ejoc.201901353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217229PMC
May 2020

Pseudo-natural products and natural product-inspired methods in chemical biology and drug discovery.

Curr Opin Chem Biol 2020 06 1;56:111-118. Epub 2020 May 1.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Straße 6, 44221 Dortmund, Germany. Electronic address:

Through evolution, nature has provided natural products (NPs) as a rich source of diverse bioactive material. Many drug discovery programs have used nature as an inspiration for the design of NP-like compound classes. These concepts are guided by the prevalidated biological relevance of NPs while going beyond the limitations of nature to produce chemical matter that could have unexpected or novel bioactivities. Herein, we discuss, compare, and highlight recent examples of NP-inspired methods with a focus on the pseudo-NP concept.
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http://dx.doi.org/10.1016/j.cbpa.2019.10.005DOI Listing
June 2020

Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor.

Angew Chem Int Ed Engl 2020 07 21;59(30):12470-12476. Epub 2020 Apr 21.

Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.
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http://dx.doi.org/10.1002/anie.202000364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383971PMC
July 2020

Macrocyclic Modalities Combining Peptide Epitopes and Natural Product Fragments.

J Am Chem Soc 2020 03 2;142(10):4904-4915. Epub 2020 Mar 2.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, 44227 Dortmund, Germany.

"Hot loop" protein segments have variable structure and conformation and contribute crucially to protein-protein interactions. We describe a new hot loop mimicking modality, termed PepNats, in which natural product (NP)-inspired structures are incorporated as conformation-determining and -restricting structural elements into macrocyclic hot loop-derived peptides. Macrocyclic PepNats representing hot loops of inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) were synthesized on solid support employing macrocyclization by imine formation and subsequent stereoselective 1,3-dipolar cycloaddition as key steps. PepNats derived from the iNOS DINNN hot loop and the AGRP RFF hot spot sequence yielded novel and potent ligands of the SPRY domain-containing SOCS box protein 2 (SPSB2) that binds to iNOS, and selective ligands for AGRP-binding melanocortin (MC) receptors. NP-inspired fragment absolute configuration determines the conformation of the peptide part responsible for binding. These results demonstrate that combination of NP-inspired scaffolds with peptidic epitopes enables identification of novel hot loop mimics with conformationally constrained and biologically relevant structure.
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http://dx.doi.org/10.1021/jacs.0c00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307906PMC
March 2020

Principle and design of pseudo-natural products.

Nat Chem 2020 03 3;12(3):227-235. Epub 2020 Feb 3.

Department of Chemical Biology, Max-Planck Institute for Molecular Physiology, Dortmund, Germany.

Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small-molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel 'pseudo-natural product' classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we identify design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small-molecule discovery.
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http://dx.doi.org/10.1038/s41557-019-0411-xDOI Listing
March 2020

Development of a PDEδ-Targeting PROTACs that Impair Lipid Metabolism.

Angew Chem Int Ed Engl 2020 03 22;59(14):5595-5601. Epub 2020 Jan 22.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Straße 11, 44227, Dortmund, Germany.

The prenyl-protein chaperone PDEδ modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited. Small-molecule inhibitors that target the PDEδ prenyl-binding site have proven invaluable in the analysis of biological processes mediated by PDEδ, like KRas cellular trafficking. However, allosteric inhibitor release from PDEδ by the Arl2/3 GTPases limits their application. We describe the development of new proteolysis-targeting chimeras (PROTACs) that efficiently and selectively reduce PDEδ levels in cells through induced proteasomal degradation. Application of the PDEδ PROTACs increased sterol regulatory element binding protein (SREBP)-mediated gene expression of enzymes involved in lipid metabolism, which was accompanied by elevated levels of cholesterol precursors. This finding for the first time demonstrates that PDEδ function plays a role in the regulation of enzymes of the mevalonate pathway.
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http://dx.doi.org/10.1002/anie.201913904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154537PMC
March 2020

Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor.

Angew Chem Int Ed Engl 2020 03 24;59(14):5721-5729. Epub 2020 Jan 24.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

Chemical proteomics is widely applied in small-molecule target identification. However, in general it does not identify non-protein small-molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology.
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http://dx.doi.org/10.1002/anie.201913712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154763PMC
March 2020

Identification of Quinolinols as Activators of TEAD-Dependent Transcription.

ACS Chem Biol 2019 12 2;14(12):2909-2921. Epub 2019 Dec 2.

Department of Multi-Modal Molecular (M3) Biology , Institute of Molecular and Cell Biology , 61 Biopolis Drive , 138673 Singapore.

The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the vertebrate downstream effectors of the Hippo signaling pathway that controls various physiological and pathological processes. YAP and TAZ pair with the TEAD (TEA domain) family of transcription factors to initiate transcription. We previously identified a tractable pocket in TEADs, which has been physiologically shown to bind palmitate. Herein, a TEAD-palmitate interaction screen was developed to select small molecules occupying the palmitate-binding pocket (PBP) of TEADs. We show that quinolinols were TEAD-binding compounds that augment YAP/TAZ-TEAD activity, which was verified using TEAD reporter assay, RT-qPCR, and RNA-Seq analyses. Structure-activity relationship investigations uncovered the quinolinol substituents that are necessary for TEAD activation. We reveal a novel mechanism where quinolinols stabilize YAP/TAZ protein levels by occupying the PBP. The enhancement of YAP activity by quinolinols accelerates the wound closure in a mouse wound-healing model. Although small molecules that occupy the PBP have been shown to inhibit YAP/TAZ-TEAD activity, leveraging PBP to activate TEADs is a novel approach.
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http://dx.doi.org/10.1021/acschembio.9b00786DOI Listing
December 2019

Lipidated Stapled Peptides Targeting the Acyl Binding Protein UNC119.

Chembiochem 2019 12 19;20(24):2987-2990. Epub 2019 Nov 19.

Vrije Universiteit Amsterdam, Department of Chemistry and Pharmaceutical Sciences, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.

The acyl-binding UNC119 proteins mediate the activation and transport of various N-myristoylated proteins. In particular, UNC119a plays a crucial role in the completion of cytokinesis. Herein, we report the use of a lipidated peptide originating from the UNC119 binding partner Gnat1 as the basis for the design of lipidated, stabilized α-helical peptides that target UNC119a. By using the hydrocarbon peptide-stapling approach, cell-permeable binders of UNC119a were generated that induced the accumulation of cytokinetic and binucleated cells; this suggests UNC119a as a potential target for the inhibition of cytokinesis.
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http://dx.doi.org/10.1002/cbic.201900615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973269PMC
December 2019

Small-Molecule Inhibition of Glucose Transporters GLUT-1-4.

Chembiochem 2020 01 8;21(1-2):45-52. Epub 2019 Nov 8.

Department Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

Glucose addiction is observed in cancer and other diseases that are associated with hyperproliferation. The development of compounds that restrict glucose supply and decrease glycolysis has great potential for the development of new therapeutic approaches. Addressing facilitative glucose transporters (GLUTs), which are often upregulated in glucose-dependent cells, is therefore of particular interest. This article reviews a selection of potent, isoform-selective GLUT inhibitors and their biological characterization. Potential therapeutic applications of GLUT inhibitors in oncology and other diseases that are linked to glucose addiction are discussed.
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http://dx.doi.org/10.1002/cbic.201900544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004114PMC
January 2020

Toward the role of cholesterol and cholesterol transfer protein in autophagosome biogenesis.

Autophagy 2019 12 18;15(12):2167-2168. Epub 2019 Sep 18.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Dortmund, Germany.

A forward chemical genetic approach led to identification of autogramins as novel autophagy inhibitors. Autogramins selectively target the cholesterol transfer protein GRAMD1A (GRAM domain containing 1A). Autogramins compete with cholesterol binding to the StART domain of GRAMD1A, thereby inhibiting its cholesterol transfer activity. GRAMD1A associates with phosphatidylinositol monophosphate via its GRAM domain. GRAMD1A accumulates at autophagosome initiation sites upon starvation. This protein is involved in cholesterol distribution in response to starvation and is required for autophagosome biogenesis. Therefore, we identify a novel function of GRAMD1A and a new role of cholesterol in macroautophagy/autophagy.
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http://dx.doi.org/10.1080/15548627.2019.1666595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844521PMC
December 2019

Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3.

Angew Chem Int Ed Engl 2019 11 7;58(47):17016-17025. Epub 2019 Oct 7.

Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.

Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP-like chemical space and biological target space. These limitations can be overcome by combining NP-centered strategies with fragment-based compound design through combination of NP-derived fragments to afford structurally unprecedented "pseudo-natural products" (pseudo-NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT-1 and GLUT-3. Glupin suppresses glycolysis, reduces the levels of glucose-derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT-1 and GLUT-3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.
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http://dx.doi.org/10.1002/anie.201909518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900016PMC
November 2019