Research Group Cell Signaling and Chemical Biology
Hadian GroupIn the Hadian Lab, we study the mechanisms of Cell Death Signaling and translate these findings into future drugs using Chemical Biology and Drug Discovery approaches. We are particularly interested in deciphering the cellular mechanisms controlling Ferroptosis and characterizing regulators of Ubiquitin Signaling in Cell Death processes. In addition, we operate the Compound Screening Platform, giving us strong expertise in high-throughput biochemical screening and high-content phenotypic screening to identify disease-relevant small molecule modulators and highly selective probes.
In the Hadian Lab, we study the mechanisms of Cell Death Signaling and translate these findings into future drugs using Chemical Biology and Drug Discovery approaches. We are particularly interested in deciphering the cellular mechanisms controlling Ferroptosis and characterizing regulators of Ubiquitin Signaling in Cell Death processes. In addition, we operate the Compound Screening Platform, giving us strong expertise in high-throughput biochemical screening and high-content phenotypic screening to identify disease-relevant small molecule modulators and highly selective probes.
Our Topics
Research topics:
- Ferroptosis Research: Unraveling mechanisms and cellular regulators that induce or block ferroptosis, a regulated non-apoptotic cell-death pathway.
- Ubiquitin Signaling: Identification and characterization of protein interactions and regulators of ubiquitin signaling pathways mainly implicated in immune response, cancer development and DNA repair.
- Chemical Biology: Interrogate biological systems with small molecules to understand underlying mechanistic details.
Drug Discovery:
We collaborate with researchers at the center as well as national and international cooperation partners to custom-design assays to screen and identify novel bioactive molecules. Here, a major focus is devoted to the development of phenotypic assays for High-Content Screening (HCS) in order to better reflect the biology of the underlying disease state. We use machine learning techniques to analyze high-content images. We provide state-of-the-art equipment and screening techniques as well as oversee the in-house diversity and focussed compound libraries.
Our Research
We are interested in deciphering novel mechanisms and cellular regulators of ferroptotic cell death as well as developing tools to precisely detect ferroptosis:
- We use small molecules with known mode of action (Chemical Biology approach) and CRISPR/RNAi technologies (Genetic approach) to identify cellular regulators controlling ferroptosis.
- We develop high-content-imaging tools together with Artificial Intelligence techniques to visualize and classify ferroptosis.
Our Research concentrates on the identification and characterization of new regulators of ubiquitin signaling pathways implicated in cell death pathways:
- We investigate the functional contribution of E3 Ligases and deubiquitinases (DUBs) to cell death pathways, in particular ferroptosis.
- We utilize proteomics and yeast-2-hybrid screening to identify novel protein-protein interactions and networks in ubiquitin signaling pathways.
- We use target-based as well as high-content phenotypic screening approaches to identify small molecule modulators of ubiquitin signaling.
The Hadian lab interrogates biological systems with small molecules to develop novel therapies. In the past decade, we have initiated and collaborated on a number of drug development studies within the fields of autoimmunity, infectious disease, rare disease, cancer, and more. Several of these studies have yielded patents and are currently at different stages of the drug development pipeline.
In the following are few examples of the current drug development activities:
- The TRAF6-Ubc13 protein-protein-interaction inhibitors developed for the treatment of autoimmune diseases (Rheumatoid Arthritis, Psoriasis, and more) are currently in preclinical lead optimization—patents: WO/2018/050286 and WO/2019/180207
- The SARS-CoV-2 PLpro inhibitor acriflavine is being optimized for clinical application against beta-coronaviruses—patent: WO/2022/129210
- Repurposing of cyclosporin-A as a molecular corrector of mutant ABCA3 may be used to treat genetically caused interstitial lung disease in children
We are interested in deciphering novel mechanisms and cellular regulators of ferroptotic cell death as well as developing tools to precisely detect ferroptosis:
- We use small molecules with known mode of action (Chemical Biology approach) and CRISPR/RNAi technologies (Genetic approach) to identify cellular regulators controlling ferroptosis.
- We develop high-content-imaging tools together with Artificial Intelligence techniques to visualize and classify ferroptosis.
Our Research concentrates on the identification and characterization of new regulators of ubiquitin signaling pathways implicated in cell death pathways:
- We investigate the functional contribution of E3 Ligases and deubiquitinases (DUBs) to cell death pathways, in particular ferroptosis.
- We utilize proteomics and yeast-2-hybrid screening to identify novel protein-protein interactions and networks in ubiquitin signaling pathways.
- We use target-based as well as high-content phenotypic screening approaches to identify small molecule modulators of ubiquitin signaling.
The Hadian lab interrogates biological systems with small molecules to develop novel therapies. In the past decade, we have initiated and collaborated on a number of drug development studies within the fields of autoimmunity, infectious disease, rare disease, cancer, and more. Several of these studies have yielded patents and are currently at different stages of the drug development pipeline.
In the following are few examples of the current drug development activities:
- The TRAF6-Ubc13 protein-protein-interaction inhibitors developed for the treatment of autoimmune diseases (Rheumatoid Arthritis, Psoriasis, and more) are currently in preclinical lead optimization—patents: WO/2018/050286 and WO/2019/180207
- The SARS-CoV-2 PLpro inhibitor acriflavine is being optimized for clinical application against beta-coronaviruses—patent: WO/2022/129210
- Repurposing of cyclosporin-A as a molecular corrector of mutant ABCA3 may be used to treat genetically caused interstitial lung disease in children
Compound Screening Platform
We collaborate with researchers at the Center as well as national/international cooperation partners and custom-design screening assays for the identification of novel bioactive molecules. Here, a major focus is devoted to the development of phenotypic assays for high-content-screening (HCS) in order to better reflect the biology of the underlying disease state. We use machine learning techniques to analyze high-content images. We provide state-of-the-art equipment and screening techniques as well as oversee the in-house diversity and focused compound libraries.
Biochemical assays:
- Protein-Protein-Interaction (PPI) assays:
- AlphaScreen interaction assay (homogenous assay)
- TR-FRET (HTRF) interaction assay (homogenous assay)
- DELFIA time-resolved fluorescence assay (ELISA based assay)
- Microscale thermophoresis (MST)
- Pull down assays (GST, StrepTagII, His, GFP-Trap, etc.)
- Enzymatic assays:
- DUBs (AMC, IQF-diUb, AlphaScreen, etc.)
- Protease cleavage assay (e.g., AMC substrates)
- Kinase assays (AlphaScreen, HTRF, ELISA)
- Phosphatase assays (AlphaScreen, HTRF)
- Protein-Compound and Nucleic Acid-Compound Interactions:
- Microscale thermophoresis
Cell-based HCS/HTS assays:
- High-Content Screening (HCS) using the Operetta System:
- Stem Cell screening
- 3D cell systems
- Morphology analysis (e.g., neurons)
- Cellular profiling using Cell painting assay
- Cellular substructures (e.g., spots, organelles, etc.)
- Cellular translocation analysis (e.g., between Nucleus and Cytoplasm)
- Protein-Protein Interactions (e.g., BiFC, FRET)
- High-Content Image Analysis with specialized software and Machine Learning/Deep Learning
- High-Throughput Screening (HTS):
- Protein-Protein Interactions (NanoBRET)
- Fluorescence-based reporter assays
- Cell viability assays
- Apoptosis assays
Diversity libraries (30,000 bioactive compounds):
- ChemDiv subset
- Diversity selection of 10,000 compounds
- Approx. 50% of the compounds have the ability to cross the blood brain barrier (information from calculations)
- Enamine subset
- Diversity selection of 10,000 compound
- ChemBridge subset
- Diversity selection of 5,000 compounds
- ChemDiv Protein-Protein Interaction (PPI) subset
- Diversity selection of 5,000 compounds
- Focus on PPI inhibition
Focussed libraries:
- Prestwick FDA approved drugs
- Medchem Express FDA approved drugs
- Repurposing library
- GPCR compound library
We collaborate with researchers at the Center as well as national/international cooperation partners and custom-design screening assays for the identification of novel bioactive molecules. Here, a major focus is devoted to the development of phenotypic assays for high-content-screening (HCS) in order to better reflect the biology of the underlying disease state. We use machine learning techniques to analyze high-content images. We provide state-of-the-art equipment and screening techniques as well as oversee the in-house diversity and focused compound libraries.
Biochemical assays:
- Protein-Protein-Interaction (PPI) assays:
- AlphaScreen interaction assay (homogenous assay)
- TR-FRET (HTRF) interaction assay (homogenous assay)
- DELFIA time-resolved fluorescence assay (ELISA based assay)
- Microscale thermophoresis (MST)
- Pull down assays (GST, StrepTagII, His, GFP-Trap, etc.)
- Enzymatic assays:
- DUBs (AMC, IQF-diUb, AlphaScreen, etc.)
- Protease cleavage assay (e.g., AMC substrates)
- Kinase assays (AlphaScreen, HTRF, ELISA)
- Phosphatase assays (AlphaScreen, HTRF)
- Protein-Compound and Nucleic Acid-Compound Interactions:
- Microscale thermophoresis
Cell-based HCS/HTS assays:
- High-Content Screening (HCS) using the Operetta System:
- Stem Cell screening
- 3D cell systems
- Morphology analysis (e.g., neurons)
- Cellular profiling using Cell painting assay
- Cellular substructures (e.g., spots, organelles, etc.)
- Cellular translocation analysis (e.g., between Nucleus and Cytoplasm)
- Protein-Protein Interactions (e.g., BiFC, FRET)
- High-Content Image Analysis with specialized software and Machine Learning/Deep Learning
- High-Throughput Screening (HTS):
- Protein-Protein Interactions (NanoBRET)
- Fluorescence-based reporter assays
- Cell viability assays
- Apoptosis assays
Diversity libraries (30,000 bioactive compounds):
- ChemDiv subset
- Diversity selection of 10,000 compounds
- Approx. 50% of the compounds have the ability to cross the blood brain barrier (information from calculations)
- Enamine subset
- Diversity selection of 10,000 compound
- ChemBridge subset
- Diversity selection of 5,000 compounds
- ChemDiv Protein-Protein Interaction (PPI) subset
- Diversity selection of 5,000 compounds
- Focus on PPI inhibition
Focussed libraries:
- Prestwick FDA approved drugs
- Medchem Express FDA approved drugs
- Repurposing library
- GPCR compound library
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