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Article ; Online: The expanding role for small molecules in immuno-oncology.

Offringa, Rienk / Kötzner, Lisa / Huck, Bayard / Urbahns, Klaus

2022 Volume 21, Issue 11, Page(s) 821–840

Abstract: The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, ... ...

Abstract	The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward.
MeSH term(s)	Humans ; Immunotherapy ; Neoplasms/drug therapy ; Tumor Microenvironment ; Cytokines ; T-Lymphocytes
Chemical Substances	Cytokines
Language	English
Publishing date	2022-08-18
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-022-00538-9
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Article: Small molecules-Giant leaps for immuno-oncology.

Kötzner, Lisa / Huck, Bayard / Garg, Sakshi / Urbahns, Klaus

Progress in medicinal chemistry

2020 Volume 59, Page(s) 1–62

Abstract: Immuno-oncology therapies are revolutionizing the oncology landscape with checkpoint blockade becoming the treatment backbone for many indications. While inspiring, much work remains to increase the number of cancer patients that can benefit from these ... ...

Abstract	Immuno-oncology therapies are revolutionizing the oncology landscape with checkpoint blockade becoming the treatment backbone for many indications. While inspiring, much work remains to increase the number of cancer patients that can benefit from these treatments. Thus, a new era of immuno-oncology research has begun which is focused on identifying novel combination regimes that lead to improved response rates. This review highlights the significance of small molecules in this approach and illustrates the huge progress that has been made to date.
MeSH term(s)	Amino Acids/antagonists & inhibitors ; Amino Acids/immunology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Humans ; Neoplasms/drug therapy ; Neoplasms/immunology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/immunology ; Protein Kinases/metabolism ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology
Chemical Substances	Amino Acids ; Antineoplastic Agents ; Protein Kinase Inhibitors ; Small Molecule Libraries ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2020-01-20
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	209306-6
ISSN	1875-7863 ; 0079-6468
ISSN (online)	1875-7863
ISSN	0079-6468
DOI	10.1016/bs.pmch.2019.11.001
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Article ; Online: Small Molecules Drive Big Improvements in Immuno-Oncology Therapies.

Huck, Bayard R / Kötzner, Lisa / Urbahns, Klaus

Angewandte Chemie (International ed. in English)

2018 Volume 57, Issue 16, Page(s) 4412–4428

Abstract: Immuno-oncology therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clinical response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a ... ...

Abstract	Immuno-oncology therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clinical response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small molecules in this approach, which holds promise to provide increased benefit to cancer patients.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Humans ; Immunotherapy ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/therapeutic use
Chemical Substances	Antineoplastic Agents ; Small Molecule Libraries
Language	English
Publishing date	2018-02-22
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201707816
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Article ; Online: High-Throughput Screening and Proteomic Characterization of Compounds Targeting Myeloid-Derived Suppressor Cells.

Krumm, Johannes / Petrova, Elissaveta / Lechner, Severin / Mergner, Julia / Boehm, Hans-Henning / Prestipino, Alessandro / Steinbrunn, Dominik / Deline, Marshall L / Koetzner, Lisa / Schindler, Christina / Helming, Laura / Fromme, Tobias / Klingenspor, Martin / Hahne, Hannes / Pieck, Jan-Carsten / Kuster, Bernhard

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 9, Page(s) 100632

Abstract: Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell ... ...

Abstract	Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell population for drug discovery. Here, we characterized the baseline proteomes and phospho-proteomes of mouse MDSC differentiated from a progenitor cell line to a depth of 7000 proteins and phosphorylation sites. We also validated the cellular system for drug discovery by recapitulating and identifying known and novel molecular responses to the well-studied MDSC drugs entinostat and mocetinostat. We established a high-throughput drug screening platform using a MDSC/T cell coculture system and assessed the effects of ∼21,000 small molecule compounds on T cell proliferation and IFN-γ secretion to identify novel MDSC modulator. The most promising candidates were validated in a human MDSC system, and subsequent proteomic experiments showed significant upregulation of several proteins associated with the reduction of reactive oxygen species (ROS). Proteome-wide solvent-induced protein stability assays identified Acyp1 and Cd74 as potential targets, and the ROS-reducing drug phenotype was validated by measuring ROS levels in cells in response to compound, suggesting a potential mode of action. We anticipate that the data and chemical tools developed in this study will be valuable for further research on MDSC and related drug discovery.
MeSH term(s)	Mice ; Humans ; Animals ; Myeloid-Derived Suppressor Cells/metabolism ; High-Throughput Screening Assays ; Proteome/metabolism ; Proteomics ; Reactive Oxygen Species/metabolism
Chemical Substances	Proteome ; Reactive Oxygen Species
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100632
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Article ; Online: Extract2Chip-Bypassing Protein Purification in Drug Discovery Using Surface Plasmon Resonance.

Paiva, Ana C F / Lemos, Ana R / Busse, Philipp / Martins, Madalena T / Silva, Diana O / Freitas, Micael C / Santos, Sandra P / Freire, Filipe / Barrey, Evelyne J / Manival, Xavier / Koetzner, Lisa / Heinrich, Timo / Wegener, Ansgar / Grädler, Ulrich / Bandeiras, Tiago M / Schwarz, Daniel / Sousa, Pedro M F

Biosensors

2023 Volume 13, Issue 10

Abstract: Modern drug discovery relies on combinatorial screening campaigns to find drug molecules targeting specific disease-associated proteins. The success of such campaigns often relies on functional and structural information of the selected therapeutic ... ...

Abstract	Modern drug discovery relies on combinatorial screening campaigns to find drug molecules targeting specific disease-associated proteins. The success of such campaigns often relies on functional and structural information of the selected therapeutic target, only achievable once its purification is mastered. With the aim of bypassing the protein purification process to gain insights on the druggability, ligand binding, and/or characterization of protein-protein interactions, herein, we describe the Extract2Chip method. This approach builds on the immobilization of site-specific biotinylated proteins of interest, directly from cellular extracts, on avidin-coated sensor chips to allow for the characterization of molecular interactions via surface plasmon resonance (SPR). The developed method was initially validated using Cyclophilin D (CypD) and subsequently applied to other drug discovery projects in which the targets of interest were difficult to express, purify, and crystallize. Extract2Chip was successfully applied to the characterization of Yes-associated protein (YAP): Transcriptional enhancer factor TEF (TEAD1) protein-protein interaction inhibitors, in the validation of a ternary complex assembly composed of Dyskerin pseudouridine synthase 1 (DKC1) and RuvBL1/RuvBL2, and in the establishment of a fast-screening platform to select the most suitable NUAK family SNF1-like kinase 2 (NUAK2) surrogate for binding and structural studies. The described method paves the way for a potential revival of the many drug discovery campaigns that have failed to deliver due to the lack of suitable and sufficient protein supply.
MeSH term(s)	Surface Plasmon Resonance/methods ; Drug Discovery/methods ; Proteins ; Chromatography, Affinity ; Protein Binding
Chemical Substances	Proteins
Language	English
Publishing date	2023-10-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662125-3
ISSN	2079-6374 ; 2079-6374
ISSN (online)	2079-6374
ISSN	2079-6374
DOI	10.3390/bios13100913
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Article: Crystal structure of 5-tert-but-yl-10,15,20-tri-phenyl-porphyrin.

Flanagan, Keith J / Mothi, Ebrahim Mohamed / Kötzner, Lisa / Senge, Mathias O

Acta crystallographica. Section E, Crystallographic communications

2016 Volume 72, Issue Pt 2, Page(s) 128–132

Abstract: In the title free base porphyrin, C42H34N4, the neighbouring N⋯N distances in the center of the ring vary from 2.818 (8) to 2.998 (8) Å and the phenyl rings are tilted from the 24-atom mean plane at angles varying between 62.42 (2)-71.63 (2)°. The NH ... ...

Abstract	In the title free base porphyrin, C42H34N4, the neighbouring N⋯N distances in the center of the ring vary from 2.818 (8) to 2.998 (8) Å and the phenyl rings are tilted from the 24-atom mean plane at angles varying between 62.42 (2)-71.63 (2)°. The NH groups are involved in intra-molecular bifurcated N-H⋯(N,N) hydrogen bonds. The Ca-Cm-Ca angles vary slightly for the phenyl rings, between 124.19 (18)-126.17 (18)°. The largest deviation from the mean plane of the 24-atom macrocycle is associated with the meso carbon at the substituted tert-butyl position, which is displaced from the mean plane by 0.44 (2) Å. The free base porphyrin is characterized by a significant degree of ruffled (B 1u ) distortion with contributions from domed (A 2u ) and wave [Eg (y) and Eg (x)] modes. In the crystal, mol-ecules are linked by a number of weak C-H⋯π inter-actions, forming a three-dimensional framework. The structure was refined as a two-component inversion twin.
Language	English
Publishing date	2016-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2041947-8
ISSN	2056-9890 ; 1600-5368
ISSN	2056-9890 ; 1600-5368
DOI	10.1107/S2056989016000025
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Article: Crystal structure of [5-n-butyl-10-(2,5-di-meth-oxy-phen-yl)-2,3,7,8,13,12,17,18-octa-ethyl-porphyrin-ato]nickel(II).

Flanagan, Keith J / Mothi, Ebrahim M / Kötzner, Lisa / Senge, Mathias O

Acta crystallographica. Section E, Crystallographic communications

2015 Volume 71, Issue Pt 11, Page(s) 1397–1400

Abstract: The asymmetric unit of the title nickel(II) porphyrin, [Ni(C48H60N4O2)], contains one independent mol-ecule. The average Ni-N bond length is 1.917 (13) Å. The mol-ecules are arranged in a closely spaced lattice structure in which neighbouring porphyrins ... ...

Abstract	The asymmetric unit of the title nickel(II) porphyrin, [Ni(C48H60N4O2)], contains one independent mol-ecule. The average Ni-N bond length is 1.917 (13) Å. The mol-ecules are arranged in a closely spaced lattice structure in which neighbouring porphyrins are oriented in inversion-related dimers. The nickel(II) porphyrin is characterized by a significant degree of a ruffled (B 1u ) conformation with small contributions from saddle (B 2u ) and wave (y) [Eg (y)], as determined using normal structural decomposition. Disorder in the 2,5-di--meth-oxy-phenyl substituent was modelled over two positions with a 60% occupancy for the major moiety. One of the ethyl groups is also disordered over two positions and was modelled with the major moiety being present in 51.3% occupancy.
Language	English
Publishing date	2015-10-31
Publishing country	England
Document type	Journal Article
ZDB-ID	2041947-8
ISSN	2056-9890 ; 1600-5368
ISSN	2056-9890 ; 1600-5368
DOI	10.1107/S2056989015020058
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Article ; Online: Catalytic asymmetric dearomatizing redox cross coupling of ketones with aryl hydrazines giving 1,4-diketones.

Huang, Shenlin / Kötzner, Lisa / De, Chandra Kanta / List, Benjamin

Journal of the American Chemical Society

2015 Volume 137, Issue 10, Page(s) 3446–3449

Abstract: An asymmetric Brønsted acid catalyzed dearomatizing redox cross coupling reaction has been realized, in which aryl hydrazines react with ketones to deliver 1,4-diketones, bearing an all-carbon quarternary stereocenter in high enantiopurity. ...

Abstract	An asymmetric Brønsted acid catalyzed dearomatizing redox cross coupling reaction has been realized, in which aryl hydrazines react with ketones to deliver 1,4-diketones, bearing an all-carbon quarternary stereocenter in high enantiopurity.
Language	English
Publishing date	2015-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/ja511200j
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Article ; Online: Asymmetric catalysis on the nanoscale: the organocatalytic approach to helicenes.

Kötzner, Lisa / Webber, Matthew J / Martínez, Alberto / De Fusco, Claudia / List, Benjamin

Angewandte Chemie (International ed. in English)

2014 Volume 53, Issue 20, Page(s) 5202–5205

Abstract: The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A ... ...

Abstract	The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities.
MeSH term(s)	Catalysis ; Nanotechnology ; Organic Chemicals/chemistry ; Polycyclic Compounds/chemistry
Chemical Substances	Organic Chemicals ; Polycyclic Compounds ; helicenes
Language	English
Publishing date	2014-05-12
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201400474
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Article ; Online: The Organocatalytic Approach to Enantiopure 2H- and 3H-Pyrroles: Inhibitors of the Hedgehog Signaling Pathway.

Kötzner, Lisa / Leutzsch, Markus / Sievers, Sonja / Patil, Sumersing / Waldmann, Herbert / Zheng, Yiying / Thiel, Walter / List, Benjamin

Angewandte Chemie (International ed. in English)

2016 Volume 55, Issue 27, Page(s) 7693–7697

Abstract: A divergent approach to enantioenriched 2H- and 3H-pyrroles catalyzed by a spirocyclic phosphoric acid is reported that makes use of a Fischer-type indolization and a [1,5]-alkyl shift. Catalyzed by the chiral phosphoric acid STRIP, good to excellent ... ...

Abstract	A divergent approach to enantioenriched 2H- and 3H-pyrroles catalyzed by a spirocyclic phosphoric acid is reported that makes use of a Fischer-type indolization and a [1,5]-alkyl shift. Catalyzed by the chiral phosphoric acid STRIP, good to excellent yields and enantioselectivities could be obtained. Remarkably, biological evaluation reveals one of these novel 2H-pyrroles to be a potent but nontoxic inhibitor of the Hedgehog signaling pathway by binding to the Smoothened protein.
MeSH term(s)	Boron Compounds/chemistry ; Catalysis ; Crystallography, X-Ray ; HEK293 Cells ; Hedgehog Proteins/antagonists & inhibitors ; Hedgehog Proteins/metabolism ; Humans ; Microscopy, Fluorescence ; Molecular Conformation ; Phosphoric Acids/chemistry ; Pyrroles/chemistry ; Pyrroles/metabolism ; Pyrroles/pharmacology ; Signal Transduction/drug effects ; Stereoisomerism
Chemical Substances	4,4-difluoro-4-bora-3a,4a-diaza-s-indacene ; Boron Compounds ; Hedgehog Proteins ; Phosphoric Acids ; Pyrroles ; phosphoric acid (E4GA8884NN)
Language	English
Publishing date	2016--27
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201602932
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