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Oncogenes

Direct hit on mutant RAS

Nature Reviews Cancer volume 14, pages 8–9 (2014)Cite this article

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small molecules that can ... block the activity of oncogenic KRAS-G12C

As cysteine thiol groups form disulphide bonds, the authors used mass spectrometry to screen a disulphide-fragment library of 480 compounds for binding to KRAS-G12C. The top fragment (6H05) could also bind HRAS-G12C, but not wild-type KRAS (even though it contains three cysteine residues). Modification of 6H05 created higher potency compounds, one of which (compound 6) was used in a co-crystal structure with KRAS-G12C to enable further structure-based design. Previous studies have shown that Cys12 is near both the nucleotide-binding pocket and the switch I and switch II regions (involved in interactions with effectors such as RAF). This co-crystal structure showed that compound 6 binds Cys12 in KRAS-G12C and extends into a pocket containing switch II (the switch-II pocket (S-IIP)) but does not interact with the nucleotide-binding pocket.

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References

  1. Ostrem, J. M. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature http://dx.doi.org/10.1038/nature12796 (2013)

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Authors
  1. Sarah Seton-Rogers
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Seton-Rogers, S. Direct hit on mutant RAS. Nat Rev Cancer 14, 8–9 (2014). https://doi.org/10.1038/nrc3650

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