The Pseudo?Natural Product Rhonin Targets RHOGDI

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, methods enable coverage space, such as fragment-based design. We describe de novo combination different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented “pseudo-natural products” in an complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements NP structure but occupy areas space not covered by chemotypes, have targets. Investigation unbiased phenotypic assays target identification led first small-molecule ligand RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits binding RHOGDI1 chaperone GDP-bound GTPases alters subcellular localization GTPases.