Drugging All RAS Isoforms With One Pocket

Abstract

Activating mutations in the three human RAS genes, KRAS, NRAS and HRAS, are among the most common oncogenic drivers in human cancers. Covalent KRAS^G12C inhibitors, which bind to the switch II pocket in the ‘off state’ of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS^G12C-driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the ‘on state’ have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

Keywords: :

• BI-2852
• GTPase
• KRAS
• small molecule inhibitors

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Author contributions

D Kessler, J Böttcher and G Fischer designed the experiments, which were performed by S Döbel, M Hinkel, B Müllauer and A Weiss-Puxbaum. Data analysis were performed by D Kessler, J Böttcher, G Fischer and A Bergner performed the pocket plasticity and water analysis. D Kessler and DB McConnell drafted and edited the manuscript.

Acknowledgments

The authors would like to thank M Gmachl, A Mantoulidis, L Martin, M Mayer, A Gollner, B Wolkerstorfer and A Zöphel for their fundamental work in the project; I Vorwahlner, M Pearson, J Quant and N Kraut for their support, the opnMe.com team for providing the BI-2852 on the collaboration platform and A Waterson, J Phan and SW Fesik at Vanderbilt University, TN for the fruitful collaboration to target KRAS. We thank the staff at beamline X06SA at the Swiss Light Source, Paul Scherrer Institut, Villigen, Switzerland, for support and the Expose GmbH for crystallographic data collection.

Financial & competing interests disclosure

This work was supported by the Austrian Forschungsförderungsgesellschaft (FFG) (grant nos. 854341, 861507, 867897 and 874517) (‘Basisprogramme’). All authors are currently employees of Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.