Related Experiment Video

Updated: Nov 12, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

5.9K

One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS

Juergen Ramharter1, Dirk Kessler1, Peter Ettmayer1

  • 1Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.

Journal of Medicinal Chemistry
|March 15, 2021
PubMed

Insights

A novel "foot in the door" strategy uses single atoms to inhibit KRAS-SOS1 protein-protein interactions. This approach led to the discovery of BI-3406, showing potential in treating KRAS-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS is a key oncogenic driver in many human cancers, regulated by protein-protein interactions (PPIs).
  • The KRAS-SOS1 interaction is essential for KRAS activation but presents a challenging target due to its large interface and high affinity.

Purpose of the Study:

  • To investigate a novel strategy for inhibiting challenging PPIs, specifically the KRAS-SOS1 interaction.
  • To discover and characterize a new inhibitor targeting the KRAS-SOS1 pathway.

Main Methods:

  • Computational and medicinal chemistry approaches to design small modifications at the KRAS-SOS1 interface.
  • Synthesis and biological evaluation of the novel inhibitor BI-3406.
  • In vivo efficacy studies in xenograft models of KRAS G13D mutant colorectal cancer, often in combination with EGFR inhibitors.

Main Results:

  • The strategic addition of a single atom between KRAS and SOS1 successfully converted activators into inhibitors.
  • Discovery of BI-3406, a potent inhibitor of the KRAS-SOS1 interaction.
  • BI-3406 demonstrated in vivo efficacy against KRAS G13D mutant colorectal tumors when combined with afatinib.

Conclusions:

  • A "foot in the door" approach with minimal modifications can effectively inhibit challenging PPIs like KRAS-SOS1.
  • BI-3406 represents a valuable tool for exploring SOS1 biology and offers a potential therapeutic strategy for KRAS-driven cancers.
  • This work challenges the necessity of large molecules for disrupting difficult PPIs.

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.3K
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

9.0K

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.7K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
4.7K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.0K
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
3.2K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.0K