ESR1: 3D Fragments with small aliphatic rings

rHost: VU University Amsterdam, The Netherlands
Academic supervisors: Dr. Maikel Wijtmans and prof. dr. Iwan de Esch (VU University Amsterdam)
Researcher: David Hamilton

Download the full description of this project: ESR1: 3D Fragments with small aliphatic rings

3D Fragments with small aliphatic rings

Fragment screening libraries and high-throughput screening libraries both have an overwhelming prevalence of two-dimensional molecules containing planar aromatic rings. It is thought that the introduction of more 3D-character into a library may make it possible for screening compounds to interact with more complex targets such as PPIs or other as yet-unknown target classes. As the four-membered cyclobutyl motif is by far the most underrepresented of the small aliphatic ring structures, it offers an unexplored niche in the pursuit of 3D fragments.

The aim of this project is to develop methodology towards the design and synthesis of novel 3D fragments – with a particular focus on the cyclobutyl motif. This chemistry is then used to enumerate a chemically and spatially diverse library of 3D fragments containing four-membered rings.

Our first approach involves enaminone intermediates which can be furnished further prior to or following reduction to the corresponding amino alcohol. Our second approach involves the generation of enone intermediates followed by the addition of polar groups via nucleophilic addition and subsequent reduction. Both approaches begin with acyclic precursors and generate small highly water-soluble fragments – which, unlike the lipophilic hits that are more common after/during High-Throughput Screening, are ideal starting points for drug-discovery cascades.

Once a library of fragments has been synthesised, the molecular shape of its members will be analysed using principle moment of inertia plots (PMI) – a measure of 3D shape. We hope to show that we can supply a novel three-dimensional fragment library that gives the medicinal chemist access to uncharted chemical space, and make these compounds available for screening against an array of different targets.

The FragNet consortium offers a wealth of networking opportunities, which in the context of this project has produced two ongoing collaborations. The first, with academic partner RCNS Hungary, focuses on the design of electrophilic warheads for covalent approaches to drug discovery. The second, with industrial biotech partner ZoBio, Netherlands, is a more MedChem-based project that aims to develop a screening hit against HSP70 into a potent lead. In this project, ESR1 offers synthetic and design contributions, whilst fellow FragNet colleagues ESR5 and ESR11 perform biophysical/biochemical screening support and computational aid, respectively.

Publications and Dissemination:

• “Enone-based cyclobutyl fragment library design and synthesis, screening results and hit elaboration” – ULTIMATE Project, European Union’s Horizon 2020 research and innovation programme under grant agreement No. 777828. Ongoing work.

• “Enaminone-based cyclobutyl fragment library design and synthesis, screening results and hit elaboration.” Ongoing work. • “Potential of cyclobutenaminone scaffolds as electrophilic warheads for covalent-binding approaches to drug discovery.” Ongoing work.

• “Identification and optimisation of allosteric inhibitors targeting the molecular chaperone HSP70.” Ongoing work.

• Lectured to 2nd year BSc Pharmaceutical Sciences students and provided research content for synthesis practical courses.

• Poster presentation at the national CHAINS conference in Veldhoven, Netherlands (December 2018)

• Poster presentation at the Fragments 2019 conference in Cambridge, UK (March 2019)

Other projects:


Contact details

Please contact us at:

FRAGNET Coordinator
VU University Amsterdam
The Netherlands

Funded by

Marie Curie Actions

EU Horizon 2020

European Union