RESEARCH: CANCER
FOLDING PROJECT #16773 PROFILE

KRAS is a gene often messed up in cancers, making them grow out of control. It's hard to treat because it binds tightly to molecules. This project looks at how a protein called VHL interacts with KRAS, hoping to find new ways to 'glue' them together and turn off KRAS.

Note: This TLDR is a simplication and may not be 100% accurate.

KRAS is one of the most frequently mutated oncogenes in human cancers, driving uncontrolled cell growth through persistent activation of the MAPK and PI3K signaling pathways.

Despite decades of effort, KRAS has long been considered “undruggable” due to its smooth surface and high affinity for GTP/GDP, which make traditional small-molecule inhibition extremely difficult.

The concept of molecular glues offers a transformative strategy by promoting or stabilizing interactions between KRAS and specific E3 ligases or regulatory partners, leading to selective degradation or allosteric modulation of KRAS.

These projects aim to discover the PPI between VHL and wild type and the G12 mutants.

Further, the novel PPI can aid the discovery of the novel molecular glue compunds that target KRAS.

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KRAS

Kirsten rat sarcoma viral oncogene homolog

KRAS is a gene that can become mutated and cause uncontrolled cell growth, leading to cancer. It's a common target for cancer research because of its role in driving tumor development.

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oncogenes

Genes that have the potential to cause cancer when mutated or overexpressed.

Oncogenes are genes that can promote the development of cancer. When they become mutated or overactive, they can lead to uncontrolled cell growth and division.

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MAPK

Mitogen-activated protein kinase

The MAPK pathway is a crucial signaling cascade involved in various cellular processes, including cell growth, differentiation, and survival. It's often dysregulated in cancer.

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PI3K

Phosphoinositide 3-kinase

PI3K is another important signaling pathway involved in cell growth, proliferation, and survival. It's often activated in cancer cells, contributing to tumor development.

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GTP/GDP

Guanosine triphosphate / Guanosine diphosphate

GTP and GDP are molecules that play a vital role in cellular signaling and energy transfer. KRAS relies on these molecules to regulate its activity.

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molecular glues

A class of drug that promotes interactions between proteins, leading to degradation or modulation of target proteins.

Molecular glues are a novel approach to drug development that aims to stabilize interactions between proteins. They can be used to degrade or modulate the activity of disease-causing proteins, such as KRAS.

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E3 ligases

Enzymes that play a crucial role in protein degradation by marking proteins for destruction.

E3 ligases are enzymes that tag proteins with ubiquitin, a small protein that marks them for destruction. This process is essential for removing damaged or unwanted proteins from cells.

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PPI

Protein-protein interaction

PPI refers to the interactions between different proteins. Understanding these interactions is crucial for comprehending cellular processes and developing new therapies.

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VHL

Von Hippel-Lindau tumor suppressor gene

VHL is a tumor suppressor gene that plays a role in regulating cell growth and preventing cancer development. Mutations in VHL can lead to various cancers.

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G12 mutants

KRAS mutations at the glycine-12 position.

G12 mutants are specific types of KRAS mutations that occur at the glycine-12 amino acid. These mutations are common in various cancers and contribute to uncontrolled cell growth.