2. Academic Validation
  3. Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras

Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras

  • J Med Chem. 2025 May 8;68(9):9129-9161. doi: 10.1021/acs.jmedchem.4c02929.
Charles W Parry 1,  Francesca Pellicano 1,  Alexander W Schüttelkopf 1,  Kim S Beyer 2,  Justin Bower 1,  Amy Bryson 1,  Kenneth Cameron 1,  Nichole M Cerutti 1,  Jonathan P Clark 1,  Stuart C Davidson 1,  Keneth Davies 1,  Martin J Drysdale 1,  Jeffrey Engelman 3,  Anna Estevan-Barber 1,  Andrea Gohlke 1,  Christopher H Gray 1,  Daniel A Guthy 2,  Min Hong 4,  Alana Hopkins 1,  Luke D Hutchinson 1,  Jennifer Konczal 1,  Michel Maira 2,  Duncan McArthur 1,  Mokdad Mezna 1,  Heather McKinnon 1,  Ridvan Nepravishta 1,  Nils Ostermann 2,  Camila C Pasquali 1,  Katie Pollock 1,  Angelo Pugliese 1,  Nicholas Rooney 1,  Niko Schmiedeberg 2,  Paul Shaw 1,  Camilo Velez-Vega 3,  Christopher West 1,  Ryan West 1,  Frederic Zecri 3,  John B Taylor 1
Affiliations

Affiliations

  • 1 Cancer Research Horizons, CRUK Scotland Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, U.K.
  • 2 Novartis Institute for BioMedical Research, Fabrikstrasse 2, Novartis Campus, CH-4056 Basel, Switzerland.
  • 3 Novartis Institutes for BioMedical Research, Inc., 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 4 NCI RAS Initiative, Frederick National Laboratory for Cancer Research, P.O. Box B, Frederick, Maryland 21702, United States.
PMID: 40162713 DOI: 10.1021/acs.jmedchem.4c02929
Abstract

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 KRasG12C, 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173460
    Ras Inhibitor
    Ras