Synthesis of a thiophene-based fluorinated library applied to fragment-based drug discovery via19F NMR with confirmed binding to mutant HRASG12V

Abstract

Thiophene containing drugs have been developed and show up among many important drugs currently in the market, like Plavix®, Cymbalta® and Tomudex®. However, this important organic group is still not present in the fluorine fragment libraries found in the literature. To fix this and contribute to increasing the structural diversity of fragment libraries, we synthesized a fluorinated, bicyclic, thiophene-based fragment library in a modular fashion to be screened via ligand observed ¹⁹F NMR against drug targets. For certain compounds in the synthesized library, binding was detected against the HRAS mutant G12V, a notoriously undruggable cancer target, and further confirmed with ¹⁵N HSQC NMR experiments. To exclude the possibility that the binding was promiscuous, the best binding fragment was screened against an unrelated protein, RNase 5 and was shown to be a non-binder.