KRAS Binders Hidden in Nature.

Andreas Bergner,Andreas Mantoulidis,Wolfgang Hela,Roland Kousek,Barbara Müllauer,Bernhard Wolkerstorfer,Gerhard Fischer,Gabriella Siszler,Andreas Gollner,Laetitia J Martin,Moriz Mayer,Xiaoling Cockcroft,Dirk Kessler,Darryl B Mcconnell

doi:10.1002/chem.201902810

Andreas Bergner, Andreas Mantoulidis + Show 12 more

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https://doi.org/10.1002/chem.201902810

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Abstract

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 KRASG12D, 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.

Highlights

Natural products have proven to be a rich source of molecular architectures for drugs
The existence of two pockets on the surface of KRAS has been discovered, which could potentially be amenable to small-molecule drug discovery.[5]
We describe an integrated approach to screening natural products in which virtual screening of natural products has been combined with elements of fragment-based screening,[7] the use of structure-activity relationships (SAR) by NMR,[8] and structure-based drug discovery[9] to uncover natural-productbased KRAS binders

Summary

Introduction

Natural products have proven to be a rich source of molecular architectures for drugs. At the time of the virtual screening campaign, only one X-ray co-crystal structure of a ligand bound to the active form of KRAS had been reported.[5b] Due to ambiguity in the electron density for the proposed binding mode in this structure, we decided instead to use the published GDP-KRAS structure (PDB code 4EPV) with indole 7 bound as published by the Fesik group,[5a] as a surrogate for GTP-KRAS.

Results

Conclusion