KRAS Binders Hidden in Nature

Natural products have proven to be a rich source of molecular architectures for drugs. Here, an integrated approach to natural product screening is proposed, which uncovered eight new natural product scaffolds for KRAS—the most frequently mutated oncogenic driver in human cancers, which has remained thus far undrugged. The approach combines aspects of virtual screening, fragment‐based screening, structure‐activity relationships (SAR) by NMR, and structure‐based drug discovery to overcome the limitations in traditional natural product approaches. By using our approach, a new “snugness of fit” scoring function and the first crystal‐soaking system of the active form of KRAS(G12D), the protein–ligand X‐ray structures of a tricyclic indolopyrrole fungal alkaloid and an indoloisoquinolinone have been successfully elucidated. The natural product KRAS hits discovered provide fruitful ground for the optimization of highly potent natural‐product‐based inhibitors of the active form of oncogenic RAS. This integrated approach for screening natural products also holds promise for other “undruggable” targets.