Dr. Félix Torres, ETH Zürich, Laboratory of physical chemistry, Switzerland
Prof. Kristaps Jaudzems, LIOS, Riga, Latvia
In August 2021, Félix, together with Prof. Roland Riek and Matthias Bütikofer, filed a patent on “target-ligand interaction detection and characterization by photo-CIDNP NMR”. To extend the chemical space of compatible molecules with the newly developed screening method, Félix had to explore which molecules are susceptible to yield photo-CIDNP polarization.
To collect data to design photo-CIDNP compatible fragment libraries, Félix visited the group of Prof. Kristaps Jaudzems at our medicinal chemistry partner site, the Latvian Institute of Organic Synthesis in Riga, Latvia(LIOS), to test a selection of molecules offered by EU-OPENSCREEN. The photo-CIDNP NMR spectra of 917 molecules were recorded, of which 137 showed strong and 202 showed moderate signal enhancements.
A subset of 102 best-polarized compounds was screened against PIN1, an important target in oncology. PIN1 is involved in solid tumors and is regarded as a challenging target due to its shallow active site. Although this sub-selection contained fragments in a diverse range of molecular weight (200-600 Da), the screening identified two hits. The first hit, 5-methyl-indole-2-carboxylic acid, was already reported in literature with an affinity of 20 µM. The second hit, a hydroxy-benzofuran derivative, is currently being validated. Initial results show structural similarity to the first hit. Thus, the screening with the ECBL sub-library is the first strong proof-of-concept for the photo-CIDNP screening of diversified libraries.
The analysis of the EU-OPENSCREEN library CIDNP resulted in identifying around 60 new molecular features which can serve as a molecular frame to design fragment libraries. A subset of 49 aromatic features is now used to generate a pilot library of 287 fragments. This new library has been screened against PIN1 and identified 39 hits, it will be screened in the future against K-Ras, and other hot targets to support the drug discovery effort in the pharma field. The photo-CIDNP fragment libraries will be upgraded at the end of 2022 to reach a phase II pilot of >1000 fragments.
Currently, Félix is running the start-up company, NexMR, which offers access to the photo-CIDNP screening technology and provides customers with fragment libraries specially designed to accelerate fragment-based drug design. NexMR forecasts to be able to provide photo-CIDNP overlaying technology on any Bruker instrument by the end of 2023 and diversify its photo-CIDNP fragment library to 100’000 compounds within the next 3 years.