KRAS Binders Hidden in Nature

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.

Mechanism of activation and the rewired network: New drug design concepts

“…120 Soaking the crystal with compound 2 yielded a 1.9 Å resolution structure. 261 Co-crystallization obtained 1.57 Å resolution dimer, with an interface resembling that observed with BI-2852 and earlier proposed by modeling and MD simulations of active KRas4B molecules. 262 Mutant Ral GTPases were also targeted by drugs binding to their GDP-bound state exploiting a new pocket 263 which displays a KRas G12C -like mutation.…”

“…Subsequent dimeric Switch I/II compound 2 pocket binders stabilized the active KRas4B G12D dimers with a K D of 3.8 µM 120 . Soaking the crystal with compound 2 yielded a 1.9 Å resolution structure 261 . Co‐crystallization obtained 1.57 Å resolution dimer, with an interface resembling that observed with BI‐2852 and earlier proposed by modeling and MD simulations of active KRas4B molecules 262 …”

Oncogenic KRAS G12D mutation promotes dimerization through a second, phosphatidylserine–dependent interface: a model for KRAS oligomerization

“…This is in contrast to the β–β interface observed in the crystal structure of the same mutant. 27 Using our NMR methodology, we also showed that the small molecule BI-2852 (ref. 37 ) stabilizes a β–β KRAS–G12D dimer in the membrane-associated state, shifting the conformational equilibrium toward a non-functional state on the membrane.…”

“…To date the KRAS ab interface is unique to the G12D mutant on the membrane, whereas crystalline states have captured snapshots of G12D monomers (PDB IDs: 6GOF, 5USJ) and a distinct b-b dimer (PDB ID: 6QUU). 27 A recent crystal structure of KRAS Q61H (PDB ID: 6MNX) also displayed an almost identical b-b interface in the crystalline state. 28 We believe that this dynamic nature of KRAS is crucial for its biological function as a molecular switch, and that disease-associated mutations could alter the conformational landscape of KRAS dimerization as well as membrane association.…”

KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations

“…S4 ) ( e.g. PDB IDs: 6quu 26 ; 6gj7 27 ; 6mqg 28 ; 6bof 29 ; 6qux 26 ; 6quw 26 ; 6quv 26 ). Overall these S 1 and S 2 conformations appear similar; however, with S 2 switch-I is in more open conformation at the beginning of the switch (residues D30–D33) and also α2-helix is more stable with this state.…”