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RAS Drug Discovery

Model of a RAS-RAF complex on a membrane

Credit: Matt Holderfield, NCI RAS Initiative

The goal of the Drug Discovery group is to develop assays that will measure aspects of RAS biology upon which human cancer cells depend. These assays comprise both phenotypic (i.e., cell-based) and molecular (in vitro) screens.

The cell-based screens developed utilizing RAS-dependent cell lines created by Mariano Barbacid, CNIO, Madrid, allow selection of molecules that preferentially inhibit cells expressing mutant RAS. Our in vitro screens focus on:

  • KRAS-lipid interactions,
  • KRAS-effector protein-protein interactions, and
  • KRAS dependent activation of effector pathways.

Successful assay formats are being made available to academic and commercial organizations for use in high-throughput screening programs that we hope will yield drugs useful in treating human cancers.

Our Progress

Our group has developed and validated assays suitable for high-throughput screening of libraries of compounds to discover tool molecules and drug candidates.

Our in vitro biochemical assays are qualified for finding molecules that affect RAS-effector and RAS-lipid interactions, as well as those that affect GTP hydrolysis.

Our group’s cell-based assays are validated for screening based on RAS-dependent growth, RAS effector (MEK/ERK) activation, RAS-effector binding, and RAS localization.

Our Projects

  • High-throughput screens of small molecule libraries
  • Validation of hit/lead molecules with secondary screens
  • Synthesis and testing of lead compounds to improve potency
  • Transfer of screening technologies to academic and industrial partners

Tools We Use

  • Mouse embryonic fibroblasts engineered to be dependent on single alleles of RAS
  • Tool compounds and approved drugs
  • Nanodiscs
  • Fully-processed KRAS protein


The Drug Discovery Group has collaborated with:

Debbie Morrison
National Cancer Institute

Karla Satchell
Northwestern University

Daiichi Sankyo

William Garland
Tosk, Inc.

Cameron Pitt
KyRAS Therapeutics


For more information about RAS Drug Discovery, contact Jim Hartley,

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