Bach Group

We apply fragment-based drug discovery (FBDD) on disease-relevant protein-protein interactions (PPIs) in order to evaluate the druggability of selected targets and identify novel chemical probes and therapeutic principles

 

 

 

 

 

 

 

 

 

 

 

The PPI targets we focus on are involved in redox signalling, oxidative stress, and inflammation - both inside and outside the central nervous system (CNS). Thereby, they play important roles in numerous and various diseases such as multiple sclerosis, stroke, acute lung inflammation, rheumatoid arthritis, and some cancers.

Our main targets are Keap1, which regulates Nrf2 and thereby the endogenous antioxidant response, and the superoxide-generating multi-subunit enzyme complex NADPH oxidase 2 (NOX2). Recently, we initiated work on the cytokine tumor necrosis factor (TNF); and new side projects include novel cancer-related PPI targets.

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.

 

 

 

  1.  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).
  2. 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, 2021, J. Med. Chem; see also Practical Fragments blog) and MAX IV’s Science highlight. Secondly, we have screened our commercial library of 2,500 fragments and optimized the compounds by X-ray-crystallography and medicinal chemistry (on-going). Thirdly, we screened the Diamond Light Source’s XChem library by X-ray crystallography and are currently optimizing the hits.

  3. 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 biological assays (on-going)

  4. 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).

5. We are also engaged in many collaboration projects: For example, we have used SPR to characterize protein-protein interactions related to KDM5B (Dorosz et al, 2019, Sci Rep), NEMO (Jussupow et al, 2020, Sci Adv), and CaMKIIa (Leurs et al, 2021, PNAS USA). Also, we contributed with LC-MS pharmacokinetic data to a small-molecule obesity study (Grunddal et al, 2021, Mol Metab), and recently, we designed and synthesized novel Cas9 inhibitors by using a fragment-inspired deconstruction-reconstruction optimization strategy of a screening hit (Lee and Tran et al, 2022, J Med Chem).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Medicinal chemistry, SPR* and biochemical/biophysical 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 cell assays and disease models by collaborators in Denmark (University of Copenhagen, University of Southern Denmark, Aarhus University), Sweden (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

Recently, we joined UBIMOTIF – a Marie Sklodowska-Curie Innovative Training Network (MSC-ITN) – focusing on the ubiquitin system and E3 ligases and led by Prof. Jakob Nilsson; and initiated our collaborative project on TNF with Prof. Mads H. Clausen (Technical University of Denmark).

You can follow us on Twitter and Instagram (see also links in bottom of the page)

 

 

 

 

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

  • Frederik Wong Christensen (Nov 2020 – Aug 2021)
  • 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:

  • Lundbeck Foundation (Fellowship and Ascending investigator grants)
  • Independent Research Fund Denmark (Project 2 grant with Prof. Clausen)
  • MSC-ITN (UBIMOTIF) (PhD stipend with Prof. Jakob Nilsson)
  • BioInnovation Institute (BII) (Proof of concept grant)
  • China Scholarship Council
  • HALOS Cross Border Research Grant
  • Torben and Alice Frimodt's Foundation
  • Simon Spies Foundation
  • Hørslev Foundation
  • Augustinus 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.

- Examples of Master Thesis Projects:

1. Fragment-based drug discovery on protein-protein interactions (pdf)

2. Mechanism of action studies of p47phox inhibitors (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 leader

Group Leader

Anders Bach
Associate Professor

Phone +45 2128 8604
anders.bach@sund.ku.dk

Group members

Name Title Phone E-mail
Anders Bach Associate Professor +4535336242 E-mail
Dilip Narayanan Assistant Professor +4535330514
Jie Zang Postdoc   E-mail
Marie Elodie Hélène Cadot PhD Fellow +4535333819 E-mail
Niels Guldager Master Thesis Student   E-mail

Chunyu Lin, PhD student

Yuting Qin, PhD student