Oxidative stress plays a crucial role in numerous diseases and pathological processes such as inflammation and neurotoxicity. As targets, we focus on the adaptor protein Keap1, which regulates the endogenous antioxidant response, and the superoxide-generating multi-subunit enzyme complex NADPH oxidase 2 (NOX2).
We screen our libraries of fragments (small substructures of drug like molecules) by biochemical and sensitive biophysical methods (FP, SPR, ligand-based NMR). Promising hits are optimized into lead compounds by medicinal chemistry, X-ray crystallography, and pharmacological assays.
- For Keap1, we have analysed current literature inhibitors for their ability to cross the blood-brain barrier (Pallesen et al, 2018, J Med Chem). This was followed by a comparative assessment study, where the known compounds were tested in a range of assays to validate and compare their activity towards Keap1. Interestingly, about half of the reported Keap1 inhibitors were found to be false positives (Tran and Pallesen et al, 2019, J Med Chem and Derek Lowe’s blog).
- We have also addressed Keap1 by FBDD pursuing three strategies: First, we deconstructed the known compounds into a target-biased library of 77 fragments and tested them for Keap1 binding using four orthogonal biophysical assays. The binding modes of key fragment hits where determined by X-ray crystallography, which allowed us to merge two fragments into novel compounds with high affinities to Keap1 (Pallesen et al, J. Med. Chem, accepted, in press). Secondly, we have screened our commercial library of 2,500 fragments and optimized the compounds by X-ray-crystallography and medicinal chemistry (on-going). Recently, we screened the Diamond Light Source’s XChem library by X-ray crystallography and are currently optimizing the hits.
- Recently, we applied FBDD to develop novel protein-protein interaction inhibitors of the p47phox subunit of NOX2. We screened our 2,500 fragments by fluorescence polarization (FP) and thermal shift assay (TSA) followed by surface plasmon resonance (SPR) validation. Biostructural studies by NMR and SAXS indicated that two fragments bound to two separate binding sites in the elongated conformation of p47phox, and the design of dimeric inhibitors thereby resulted in potent compounds (Solbak et al, 2020, J Med Chem). Since then, the compounds have been further optimized and tested in various
- PDZ domains are intriguing but challenging drug targets. Recently, we investigated the druggability of PSD-95’s PDZ1-2 domain by fragment-based screening and a computational method. This resulted in new fragments shown to bind the PDZ domains of PSD-95 (Zang et al, 2020, ChemMedChem).

Medicinal chemistry, SPR* and biochemical assays are core methods of our group. X-ray crystallography is performed in close collaboration with internal colleague Prof. Michael Gajhede using various beamlines in Europe, e.g. ESRF (Grenoble), EMBL (Hamburg), MAX IV (Lund)**, and Diamond Light Source (Oxfordshire). NMR for studying ligand-protein interactions is done with collaborators in Germany (Helmholtz Zentrum München) and Denmark (Technical University of Denmark), and testing in disease models by collaborators in Denmark (University of Copenhagen and University of Southern Denmark), Sweden (Lund University and Karolinska Institute), and USA (University of Miami).
- *See SelectScience interview about our Pioneer system and how we use it
- **See HALOS interview about X-ray experiments at MAXIV related to p67phox/NOX2
We are also engaged in collaborative projects within brain cancer (with Asc. Prof. Petra Hamerlik, Danish Cancer Society Research Center) and bacterial targets (with Prof. Morten O. A. Sommer, Technical University of Denmark).
Postdocs
- Dilip Narayanan (June 2016 – March 2020)
- Jakob Staun Pallesen (July – Nov 2019)
- Sara Marie Øie Solbak (March 2016 – March 2019)
PhD students
- Jie Zang (Nov 2017 – Feb 2021)
- Jakob Staun Pallesen (Jan 2016 – June 2019)
- Giuseppe Marseglia (exchange from Parma University) (Nov 2018 – April 2019)
Research Assistants
- Kim Tai Tran (May 2019 – Aug 2020)
- Lars Jakobsen Høj (Sept – Dec 2017)
MSc Students
- Felix Peters (Erasmus) (March 2020 – Feb 2021)
- Louis Martin Eichstedt Sørensen (Nov 2019 – Dec 2020)
- Munira Mohamed Shishay Hissabu (Feb – Nov 2020)
- Georgia Goutsiou (Erasmus) (March – Oct 2020)
- Kristina Olegovna Vasilyeva (Feb – Aug 2020)
- Elina Mukminova (Sept 2019 – Aug 2020)
- Martin Mariboe Olesen (Sept 2019 – Aug 2020)
- Amina Baig (Sept 2018 – March 2020)
- Dorleta Gonzalez Chichon (Sept 2018 – Aug 2019)
- Erik Bjørn Dampe (Sept 2018 – Aug 2019)
- Martina Luchini (Erasmus) (March – Aug 2019)
- Kim Tai Tran (incl. Scholar project) (Sept 2017 – April 2019)
- Nanna Haapanen (Sept 2017 – Jan 2019)
- Rosa Macarena Carrasquilla Carmona (Sept 2016 – Aug 2017)
- Lars Jakobsen Høj (Feb – Aug 2017)
- Anthony Garcia (Erasmus) (Feb – Aug 2017)
- Federico Munafo (Erasmus) (Oct 2016 – March 2017)
- Alejandro Escobar Peso (Erasmus) (Oct 2016 – Jan 2017)
- Alejandro Aguayo Orozco (Sept 2014 – Aug 2015)
- Thomas Breum Pedersen (Sept 2014 – Aug 2015)
BSc Students
- Kim Tai Tran (Jan – June 2016)
We thank the following foundations for their generous support of our research:
- BioInnovation Institute (BII)
- China Scholarship Council
- HALOS Cross Border Research Grant
- Hørslev Foundation
- Augustinus Foundation
- Lundbeck Foundation
- A.P. Møller Foundation
If you are you interested in doing a master thesis project in the group, please send your CV, grades and motivations to anders.bach@sund.ku.dk for further discussions. We have projects both within chemistry and biological areas of drug discovery.
- See examples of Master Thesis Projects here (pdf).
Currently we have no open PhD and postdoc positions in our group, but we are always interested in hearing from talented and potential candidates. If you are interested in becoming part of our group please send your CV and motivations to anders.bach@sund.ku.dk
Group members
Name | Title | Phone | |
---|---|---|---|
Chunyu Lin | Enrolled PhD Student | ||
Frederik Wong Christensen | Master student | ||
Jie Zang | Postdoc | ||
Yuting Qin | Enrolled PhD student |