How did you get interested in Medicinal Chemistry?

As I wrote in my very recently published scientific autobiography in the Serie Lives in Chemistry (https://l-i-c.org/horst-kessler.html), I was trained as Organic Chemist (synthesis of small ring compounds) at the University of Tübingen under the guidance of Eugen Müller in my Ph.D. After my thesis I studied rapid intramolecular rearrangements by NMR-spectroscopy. After habilitation I obtained a call to the Johann-Wolfgang-Goethe-University in Frankfurt as Full-Professor at the age of 31 years.

There I became interested in peptide synthesis and conformational studies by NMR. After 18 years in Frankfurt I moved as professor of Organic Chemistry and Biochemistry to the Technical University Munich (TUM). We developed a number of novel multidimensional NMR techniques in combination with molecular dynamics to achieve reliable pictures of peptide conformations. This knowledge was used to design biological active conformationally restrained peptides with super-activities and receptor subtype selectivity. 

My interest shifted to application of those peptides as drugs of for molecular imaging (after radiolabeling for SPECT and PET). Finally, my main interest was in the design of orally active peptides (via conformational restraints and multiple N-methylation.

Where are you currently working and what is your current position?

After my official retirement in 2008, I became a member of the IAS and member of the Senior Excellence Faculty and was granted to do lab work until 2019. 

My main interest was the development of super-active and selective ligands for RGD-recognizing the cell-adhesion receptors, the integrins. We were able to develop (in our opinion the ligands with highes affinities (sub-nanomolecular) and very high selectivities (several orders of magnitude) against other integrin subtypes (for αvβ3, αvβ6, αvβ8, α5β1 and αIIbβ3). Some of these ligands are now used in the clinics are in clinical phase I – III, e.g. for the detection of cancer (see trivehexin for αvβ6 or pentixafor for the the chemokine CXCR4).

My general interest was the modification of bioactive peptides in compound for medical use. For this we introduced very early the concept of conformational restraint and used it under conformational control by NMR. Peptidic drugs should be at best orally available. In some cases it was possible to pin down the essentials for oral availability.

I am 83 years old and retired. 

What do you consider your greatest achievement in your scientific career?

I  contributed to the whole field of peptides as drugs (synthesis, conformational based design, applications for Molecular Imaging) which is described in my autobiography.

What advice would you give to someone who wants to know more about your field?

As scientist one should always look for interesting new facts which are not yet fully understood. If you find out some novel features, ask how this could be converted in useful application, but do not restrain your mind too early in applications. If you do only application on a known background I would call it “technology”, not “science”.

What is the most embarrassing thing you have done in the lab while doing experiments, e.g. explosions?

As many chemists I began my interest in chemistry in my own lab (at the age of about 13 years). Nowadays it would be impossible to get all the dangerous chemicals which I used. I had a severe explosion when I was very young. My advice: “do not start with lab work when you do not fully understand what you are doing”.

Which field of medicinal chemistry do you consider the most promising for the future?

It is difficult to make predictions, especially it they are for the future.

The aim of the EuChemS Young Chemists’ Award (EYCA) is to showcase and recognize the excellent research being carried out by young scientists working in the chemical sciences. The award is intended to honour and encourage younger chemists whose current research displays a high level of excellence and distinction. It seeks to recognise and reward younger chemists of exceptional ability who show promise for substantial future achievements in chemistry-related research fields.

The deadline for nominations is 19 April 2024. Please note that only self-nominations are allowed.

EYCA finalists will present their research at the 9th EuChemS Chemistry Congress, which will be held in Dublin, Ireland, on 7-11 July 2024. The award will be presented to the winners at the congress.

More information and application on www.euchems.eu/awards/european-young-chemists-award.

Tumor hypoxia (low oxygen levels) is associated with resistance to all therapeutic approaches to treat cancers, and consequently poor patient prognosis. Hypoxia-activated prodrugs (HAPs), designed to selectively release a bioactive compound in oxygen-deficient cells, while sparing healthy tissue, represent a promising therapeutic strategy for treatment of cancers. [1,2] I will discuss our recent work to develop HAPs applied to a lysine deacetylase (KDAC) inhibitor and PROTACs. We have developed NI-Pano (CH-03), a novel hypoxia-activated version of the clinically approved KDAC inhibitor, panobinostat. We demonstrated the pre-clinical efficacy of NI-Pano, showing that it is stable in normoxic (21% oxygen) conditions but undergoes NADPH-CYP-mediated enzymatic bioreduction to release panobinostat selectively in hypoxia (

Register for free here.

#GDCh (MedChem Division), #NextGenMedChem.

References

(1) Cazares-Korner et al. ACS Chem. Biol. 2013, 8, 1451–1459.

(2) O’Connor et al. Nat. Protoc. 2016, 11, 781–794.

(3) Skwarska, Calder et al. Cell Chem. Biol. 2021, 28, 1258.

(4) Tosun, Wallabregue, Mallerman et al. JACS Au 2023, 3, 3237.

Hot Topics: Covalent Drug Discovery 2024
16^th May 2024, Virtual
Registration is now open! 
Website: https://www.rscbmcs.org/events/hottopicscdd24/

Synopsis: Covalent binding has emerged as a key strategy in contemporary drug discovery. This online, half-day meeting will bring together experts from both academia and industry to discuss recent advances in using covalent small molecules to target challenging protein targets. The BMCS Hot Topics online meetings are intended to highlight breaking areas of research in fields of science relevant to drug discovery. They will run as stand-alone half-day virtual events, 2-3 times per year. The programme will be targeted towards researchers working who would like to enhance their understanding of these nascent or developing fields.

4^th Synthesis in Drug Discovery and Development
4^th – 5^th June, Virtual
Registration is now open!
Website: https://www.rscbmcs.org/events/sddd24/ 

Synopsis: Synthesis is at the heart of drug discovery and development. The industry has increasingly demanded higher quality clinical candidates and has sought to exploit less druggable biological targets. Densely functionalised small molecules with a high degree of synthetic complexity are often the result of these demands. Successful programmes therefore require the application of innovative synthesis in all stages of discovery and development. The medicinal chemist’s toolbox is also enhanced by the introduction of novel bioisosteres, often made available only through the application of new synthetic methods. This symposium aims to celebrate the crucial role of synthesis in the success of drug discovery and development.

3rd RSC / SCI New Therapeutics for Global Health
9^th – 11^th September 2024, Cranfield Management Development Centre, Cranfield University, Milton Keynes
RSC/BMCS/SCI
Abstract submissions are now open!
Website: https://www.rscbmcs.org/events/ntgh24/

Synopsis: Tuberculosis, malaria and diseases caused by a diverse range of pathogens, including flaviviruses (eg dengue, West Nile), kinetoplastids (causative agents of Chagas disease, leishmaniasis, etc) and gut pathogens (worms, bacteria, parasites),
remain a cause of high mortality across the globe. Fortunately, an ever-improving understanding of the complex life-cycles of these disease-causing pathogens is presenting increasing opportunities for those seeking to tackle these global health problems. This meeting will focus on medicinal chemistry approaches to developing new medicines for diseases affecting global health. Keynote talks from international experts from industry and academia, alongside perspectives detailing case histories in drug discovery, will highlight the latest developments in the field whilst also showcasing the opportunity for creativity and innovation.

9^th GPCR’s in Medicinal Chemistry
2^nd – 4^th October 2024, Evotec Campus Levi-Montalchini, Verona, Italy
Registration is now open!
Website: https://www.rscbmcs.org/events/gpcrs24/ 

Synopsis: The key role of G protein-coupled receptors (GPCRs) in human disease underpins their importance to modern medicine. We were pleased to hold this 9th meeting in the series on GPCR drug discovery, which combined cutting edge medicinal chemistry with innovative structural biology and novel drug design approaches.

6^th RSC-BMCS/DMDG New Perspectives in DMPK
Monday 17^th June, 2024 Liverpool Medical Institute,
Abstract submissions and registration is now open!
Website: https://www.rscbmcs.org/events/dmpk24/  
Synopsis: Novel small-molecule-based therapeutic approaches represent a key component of the discovery landscape. The emergence of molecular glues, PROTACs, bicyclic peptides, and other novel chemistries often bring with them new challenges for drug discovery scientists; synthetic difficulty, beyond rule-of-five physicochemical properties, and complexity in the link between exposure and response, may complicate ADME characterisation and accurate human dose prediction, particularly for drugs aimed at oral administration. This meeting will provide a forum for the exchange of ideas between principal members of the DMPK research community on how we can rise to these challenges. Keynote talks from thought leaders will provide wider perspectives on how DMPK can contribute to the delivery of medicines to patients more quickly and efficiently.  There will be a balanced mix of oral and poster presentations, and networking opportunities throughout.

3rd RSC / SCI New Therapeutics for Global Health

9^th – 11^th September 2024, Cranfield Management Development Centre, Cranfield University, Milton Keynes
Abstract submissions are now open! Registration is now open!
Website: https://www.rscbmcs.org/events/ntgh24/

Synopsis: Tuberculosis, malaria and diseases caused by a diverse range of pathogens, including flaviviruses (eg dengue, West Nile), kinetoplastids (causative agents of Chagas disease, leishmaniasis, etc) and gut pathogens (worms, bacteria, parasites),remain a cause of high mortality across the globe. Fortunately, an ever-improving understanding of the complex life-cycles of these disease-causing
pathogens is presenting increasing opportunities for those seeking to tackle these global health problems. This meeting will focus on medicinal chemistry approaches to developing new medicines for diseases affecting global health. Keynote talks from international experts from industry and academia, alongside perspectives detailing case histories in drug discovery, will highlight the latest developments in the field whilst also showcasing the opportunity for creativity and innovation.