Main Menu

Small molecules, clinical trials and protein degradation: our new Head of Chemistry on 25 years in cancer drug discovery


Professor Swen Hoelder gave his inaugural lecture recently to mark his promotion to Professor at the ICR in 2020 – an event that had been postponed due to the Covid pandemic.

Posted on 26 April, 2023 by Alisa Crisp

Professor Swen Hoelder

Colleagues from across the Institute of Cancer Research joined friends and family for Professor Swen Hoelder's inaugural lecture in the BLB lecture theatre, and by video link in CBL. Uniquely, four Heads of Chemistry from the ICR were in the room at once – Professor Hoelder and his three immediate predecessors.

Dr Olivia Rossanese opened the event, reflecting that successes in science and drug discovery are often hard, and few and far between, so it is important for us to celebrate them.

Professor Hoelder has embodied the requirements for a Professorship and his academic excellence and team science has driven changes that are now benefiting patients in the clinic, said Dr Rossanese. His appointment to Head of Chemistry in 2022 was an important acknowledgement of his leadership in drug discovery science.

Professor Hoelder’s lecture highlighted how much drug discovery is a team science, and quite how many people across and outside the ICR have contributed to this body of work – beginning with his school chemistry teacher, Karl Heinz Steinhoff, who started his interest in chemistry.

This has grown from his first chemistry lab in his mother’s utility room to 25 years of drug discovery, and compounds in clinical trials.

From utility room to the ICR

Swen studied chemistry at the University of Münster, completing his PhD in organic chemistry at the Technical University in Berlin and a post-doc with Professor P.G. Schultz at the University of California.

Working at Hoechst Marion Roussel, now part of Sanofi, he really learnt the business of medicinal chemistry, working in diabetes therapies as well as kinase drug discovery.

Joining Altana Pharma was his first introduction to cancer drug discovery, where he worked on their AKT programme and on allosteric inhibitors of AKT with no selectivity problems, which progressed to in vivo proof of concepts two years later.

At a conference on PI3 kinase signalling pathways in disease, one lecture on drugging the PI3 kinome for cancer treatment caught his eye. The academic willing to take on the whole PI3 kinome was the ICR’s Professor Paul Workman.

Impressed by the creative chemistry that the team was doing, Swen soon interviewed for the role of Team Leader in Medicinal Chemistry at the ICR.

The ICR is currently making a significant investment in the Division of Cancer Therapeutics – which encompasses the Centre for Cancer Drug Discovery – with the recruitment of five new senior Faculty including roles in the Centre for Cancer Drug Discovery, the new Centre for Protein Degradation and the new Centre for Target Validation.

Current senior CCDD vacancies

Drugging kinases

Nek2 was the first project Swen worked on at the ICR, a kinase involved in the separation of the centrosomes during mitotic cell division.

Despite a promising hypothesis, RNAi studies eventually stopped the project – but not before some interesting medicinal chemistry lessons in how hard it can be to make potent inhibitors for some kinases.

Swen’s next project, on monopolar spindle protein 1 (MSP1) was initially led by Spiros Linardopoulos, then at the ICR, and also involving former ICR Head of Chemistry Julian Blagg. This project has taken an ingenious route to disrupt a ‘checkpoint’ in cell division that some cancer cells, and especially ‘triple negative’ breast cancer, become overly reliant on to keep on dividing and growing.

The MSP1 project led to the discovery of multiple series of inhibitors and ultimately the discovery of the experimental drug CCT289346, also known as BOS172722. The compound has entered a phase I trial in triple negative breast cancer, in combination with paclitaxel, and the ICR is currently seeking a new commercial partner to continue its development.

Targeting transcription

In his inaugural lecture, next Professor Hoelder turned to the story of seeking inhibitors of BCL6, a current and very exciting drug discovery project at the ICR.

BCL6 is an oncogenic transcriptional repressor – meaning it represses genes that help prevent the disease – and is an attractive target for potential B-cell lymphoma treatment. To target this transcription factor, the team wanted to find inhibitors that would block its interactions with other proteins that help it to bind other, ‘co-repressor’ proteins and so block the effects of these cancer-preventing genes.

From the start, the chemistry was challenging, but also very interesting. Combining a couple of early hit compounds was promising, but the initial ‘scaffolds’ that formed the molecular frame pushed the active molecular groups away from the target pocket on BCL6.

So the team rescaffolded, but eventually reached a plateau, where the inhibitors they were making were not potent enough. It was back to the drawing board.

But with support from researchers in our Division of Structural Biology, the team came up with a promising new avenue for further research. They showed that tricyclic compounds had high intrinsic affinity with BCL6 and gave a great step forward in potency, ultimately producing inhibitors that worked potently in the low, ‘picomolar’ range of concentration.

As well as blocking its activity, some of these compounds actually led to degradation of BCL6. The team ultimately discovered advanced degraders and inhibitors that are being used to investigate modulation of BCL6 in in vivo models of cancers.

Team science

Drug discovery is a team effort. At least three generations of the ‘Med Chem 4’ team, now led by Professor Hoelder, have contributed to the BCL6 project, including 12 chemists.

Professor Hoelder concluded his lecture by thanking everyone who has helped with this body of work and who he has had the great pleasure to work with over the years – including colleagues across the ICR, in the Centre for Cancer Drug Discovery and now in our new Centre for Protein Degradation, as well as friends and family.

Swen gave particular mention to Dr Jack Cheung, the “most productive chemist in the world”, who can magically produce 2mgs of any compound – and Dr Ben Bellenie, who joined the team as a Senior Staff Scientist and is now jointly leading the team.

And to Carol Laplain and the catering team at the Centre for Drug Discovery for a great cup of coffee every morning!


Swen Hoelder drug discovery protein degradation AKT bcl6 molecular glue degraders
comments powered by Disqus