Related Experiment Video

Updated: Aug 15, 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

5.8K

α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell

Baraa Abuasaker1, Eduardo Garrido1,2, Marta Vilaplana3

  • 1Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain.

International Journal of Molecular Sciences
|January 8, 2023
PubMed

Insights

Researchers discovered a new compound, P14B, that targets the KRAS oncogene. This compound shows promise in cancer therapy by disrupting KRAS signaling pathways and selectively impairing cancer cell viability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS mutations are prevalent in pancreatic, lung, and colorectal cancers (CRC).
  • Targeting KRAS has been challenging, with limited approved therapies for specific mutations.
  • The allosteric domain near KRAS α4-α5 helices is a potential druggable site, previously linked to calmodulin (CaM) binding.

Purpose of the Study:

  • To identify and characterize a novel compound targeting oncogenic KRAS.
  • To investigate the mechanism of action of the new compound, P14B.
  • To evaluate the therapeutic potential of P14B in cancer cells with oncogenic KRAS.

Main Methods:

  • Molecular dynamics simulations and docking processes to identify P14B.
  • Surface plasmon resonance and pulldown assays to confirm P14B binding to KRAS.
  • Assessment of downstream Ras signaling and cell viability in CRC cells.

Main Results:

  • P14B stably binds to a druggable pocket in the KRAS allosteric domain, near the α4-α5 helices.
  • P14B directly binds to oncogenic KRAS, competing with CaM.
  • P14B enhances oncogenic KRAS interactions with BRAF and C-RAF, increasing downstream signaling and impairing CRC cell viability.

Conclusions:

  • The α4-α5 helices region of KRAS is critical for regulating oncogenic KRAS signaling.
  • Drugs targeting this allosteric site, like P14B, can selectively induce cancer cell death.
  • P14B represents a promising therapeutic strategy for cancers driven by oncogenic KRAS.
Keywords:
AKTERKKRASRAFallosteric pocketcalmodulincolorectal cancerdockingmolecular dynamicssmall molecule inhibitors

More Related Videos

Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening05:54

Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening

Published on: September 5, 2018

8.7K
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.1K

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...
6.4K
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:
4.1K
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...
3.8K
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
13.5K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K
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...
5.8K