RESEARCH: CANCER
FOLDING PROJECT #16774 PROFILE

KRAS is a gene that causes cancer by making cells grow too fast. It's hard to block KRAS with drugs because its shape and how it works make this difficult. The project looks at how KRAS interacts with other proteins, hoping to find new ways to control it using 'molecular glues'. These glues could help degrade KRAS or change how it works, leading to better cancer treatments.

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 cancer. These mutations lead to uncontrolled cell growth. KRAS has been difficult to target with drugs because of its shape and how it binds to other molecules. A new strategy called 'molecular glues' aims to interact with KRAS and promote its degradation, potentially offering a new way to treat cancers driven by KRAS mutations.

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oncogenes

Genes that have the potential to cause cancer when mutated.

Oncogenes are genes that can become activated and contribute to the development of cancer. When these genes are mutated or overexpressed, they can promote uncontrolled cell growth and division, leading to tumor formation.

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MAPK

Mitogen-activated protein kinase

The MAPK pathway is a crucial signaling cascade involved in cell growth, proliferation, and differentiation. Mutations or dysregulation of this pathway can contribute to cancer development.

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PI3K

Phosphoinositide 3-kinase

The PI3K pathway is another important signaling pathway involved in cell growth, survival, and metabolism. It plays a role in cancer development through various mechanisms.

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E3 ligases

Enzymes that facilitate the ubiquitination of target proteins, marking them for degradation.

E3 ligases are enzymes that play a crucial role in protein degradation by attaching ubiquitin tags to target proteins. This tagging process marks the proteins for destruction by cellular machinery.

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molecular glues

A novel class of therapeutic agents that promote interactions between proteins.

Molecular glues are a new type of drug that works by bringing together specific proteins. This can lead to the activation or degradation of target proteins, offering a potential treatment for diseases like cancer.

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VHL

Von Hippel-Lindau tumor suppressor gene

VHL is a gene that normally acts as a tumor suppressor, helping to regulate cell growth and prevent cancer. Mutations in VHL can lead to the development of various tumors.

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PPI

Protein-protein interaction

PPI refers to the interactions between different proteins. These interactions are essential for many cellular processes, including signaling pathways and gene regulation.

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compunds

Chemicals with a defined structure and properties.

Compounds are chemical substances with a specific molecular structure. In the context of drug discovery, compounds are often screened for their ability to interact with specific targets, such as proteins involved in cancer development.