Analytical Sciences, Contributed Talk (15min)

Combining Activity Profiling with Advanced Annotation to Accelerate the Discovery of Natural Products Targeting Oncogenic Signaling in Melanoma

E. Garo1, T. Hell1, A. Rutz2,4, L. Dürr1, M. Dobrzyński3, J. K. Reinhardt1, O. Pertz3, M. Hamburger1, J. Wolfender2,4
1Division of Pharmaceutical Biology, University of Basel, 2School of Pharmaceutical Sciences, University of Geneva, 3Institute of Cell Biology, University of Bern, 4Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva

HPLC-based activity profiling is routinely used in our lab to track active compounds in plant extracts and was applied here to a project aiming to identify natural products (NPs) inhibiting oncogenic signaling in melanoma [1]. An in-house library of 2’576 plant extracts was screened in an image-based high-content assay. A total of 140 hits were found, and 44 of them were selected for activity profiling. The informed selection of extracts prior to a preparative isolation of active compounds is key to success in NP-based drug discovery, given the large number of samples to process. Linking high-quality metabolite annotations in crude extracts with activity would significantly facilitate this selection step.

We therefore combined advanced UHPLC-HRMS/MS metabolite profiling with HPLC-based activity profiling to leverage the information obtained from both approaches. This strategy was successfully applied to a subset of the library, at the level of sub-milligram amounts of crude extract. Advanced annotation and data organisation allowed the identification of compounds that were likely responsible for the activity of these extracts. The overall workflow will be presented and illustrated with selected examples of structurally diverse compounds.


[1] Lara Dürr, Tanja Hell, Maciej Dobrzyński, Alberto Matei, Anika John, Nathanja Augsburger, Gloria Bradanini, Jakob K Reinhardt, Florian Rossberg, Milos Drobnjakovic, Mahabir Gupta, Matthias Hamburger, Olivier Pertz, Eliane Garo, J. Nat. Prod. 2022, 85, 1006-1017.