Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras
Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRas<sup>G12C</sup>, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Here we report the discovery of a novel series of reversible inhibitors that bind in an enlarged version of the switch I-II pocket with nanomolar affinities. Dependent on chemotype these can either preferentially bind to the inactive or active state or bind both with similar affinity. The active-state binders inhibit the Raf interaction for wild-type Ras, and a broad range of oncogenic KRas mutants with nanomolar potency. A subseries of these molecules displays cellular inhibition of Ras-Raf binding, as well as decreased phosphorylation of the downstream protein ERK, demonstrating that potent multivariant Ras inhibitors can be accessed from this novel pocket.
Authors
- Duncan McArthur
- Luke D. Hutchinson (ORCID: https://orcid.org/0000-0002-5924-6692)
- Martin J. Drysdale (ORCID: https://orcid.org/0000-0002-3847-0556)
- Claudio Pasquali (ORCID: https://orcid.org/0009-0008-1322-2549)
- Stuart C. Davidson (ORCID: https://orcid.org/0000-0002-6673-9508)
- Kenneth Cameron
- Amy Bryson (ORCID: https://orcid.org/0000-0003-3025-2172)
- Kim S. Beyer (ORCID: https://orcid.org/0000-0002-3047-304X)
- Mokdad Mezna
- Niko Schmiedeberg
- Heather J. McKinnon (ORCID: https://orcid.org/0000-0002-7823-4240)
- John B. Taylor (ORCID: https://orcid.org/0000-0003-1876-8774)
- Jeffrey A. Engelman (ORCID: https://orcid.org/0009-0004-0775-4523)
- Frédéric J. Zécri (ORCID: https://orcid.org/0000-0002-2469-8875)
- Alexander W. Schüttelkopf (ORCID: https://orcid.org/0000-0002-9424-8730)
- Justin Bower
- Alana Hopkins
- Keneth Davies
- Min Jee Hong (ORCID: https://orcid.org/0000-0002-5126-2268)
- Camilo Velez‐Vega (ORCID: https://orcid.org/0000-0002-2803-9770)
- Katie Pollock (ORCID: https://orcid.org/0000-0002-3733-3162)
- Nils Ostermann (ORCID: https://orcid.org/0000-0002-3391-1228)
- Ridvan Nepravishta (ORCID: https://orcid.org/0000-0002-0051-762X)
- Nichole M. Cerutti
- Jennifer Konczal
- Paul Shaw (ORCID: https://orcid.org/0000-0002-6488-5288)
- Sauveur-Michel Maira (ORCID: https://orcid.org/0009-0007-7294-2653)
- Daniel Guthy (ORCID: https://orcid.org/0000-0001-5324-8585)
- Andrea Gohlke (ORCID: https://orcid.org/0000-0002-5447-5453)
- Angelo Pugliese (ORCID: https://orcid.org/0000-0002-9472-7440)
- Christopher H. Gray (ORCID: https://orcid.org/0000-0002-9895-0682)
- Ryan West
- Charles Parry (ORCID: https://orcid.org/0000-0003-0401-2693)
- Nicholas Rooney (ORCID: https://orcid.org/0009-0008-0652-4207)
- Christopher West (ORCID: https://orcid.org/0000-0002-0115-2060)
- Jonathan Clark (ORCID: https://orcid.org/0009-0003-5019-5408)
- Francesca Pellicano (ORCID: https://orcid.org/0000-0001-5355-5374)
- Anna Estevan-Barber
Institutions
- Novartis (Switzerland) (CH)
- Frederick National Laboratory for Cancer Research (US)
- Cancer Research UK Scotland Institute (GB)
- Novartis Institutes for BioMedical Research
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02929
- Citations
- 5
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Cancer Research UK
- Novartis Pharma