Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment, amelioration or prevention of cancer

Earlier this year, our client TOLREMO therapeutics nominated the clinical candidate for a chemical series that was developed together with Symeres. In this article, we spoke with Yorik Bruseker, one of our chemists, who has been involved in the project since it started at Symeres.

I'm Yorik Bruseker and I've been working at Symeres in the Netherlands for 12 years. I started as a Research Chemist in the Discovery Chemistry Department and later transferred to the Medicinal Chemistry Department, where I am currently a Senior Scientist on the TOLREMO project.

TOLREMO’s goal is to identify novel drug-resistance regulators and to develop small molecules that modulate them. This project started as a phenotypic screening (no target known) and progressed into a target-focused MedChem project, from hit finding through to lead optimization and beyond.

The team consisted of a core team of 4 to 5 chemists, working closely with our computational chemists, the ADME and analytical departments, and the team at TOLREMO. It has been a real team effort with input from everyone.

Symeres’ role was the design and synthesis of small molecules, based on the pharmacology and ADME data, and the generation of that ADME data. Additionally, we supported TOLREMO with database management and provided biobased CROs with the requested compounds.

The complexity has grown exponentially. As the scope of our projects evolves, the questions the analytical department receives are more challenging and broader than they used to be. We used to only work with small molecules. Nowadays, we make many larger molecules like macrocycles, but also molecules you can hardly detect by LCMS: very fatty ones, polar ones, and also fragment-like tiny ones. The complexity of the structures is much more diverse now than it was in the past.

Some of the asymmetric synthesis was not straightforward at first and required continuing effort to ensure the delivery of final compounds. We also dedicated time to ensure that the various PK and PD models (performed in various labs around the world) received our compounds on time to generate the data the project needed.

We took this early-stage, phenotypic MedChem approach and transformed it into an increasingly advanced target-driven project. The results were some extremely promising compounds and a clinical candidate that will hopefully advance to the clinic. I really enjoyed how we built a great, multidisciplinary team between TOLREMO and Symeres, and we learned a lot along the way.

Recently published patents around this nomination are WO 2020/127200 A1 and WO 2021/064142 A1

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Development Centres of Excellence Network Lead Optimization Hit Generation Lead Optimization

Development Centres of Excellence Network Lead Optimization Hit Generation Lead Optimization
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