RESEARCH: CANCER
FOLDING PROJECT #16775 PROFILE

The project relates to finding new ways to treat cancer caused by mutations in the KRAS gene. KRAS is hard to target with drugs because its shape makes it slippery. This project focuses on using molecules that act like glue, binding KRAS to other proteins that can destroy it or change how it works.

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 codes for a protein involved in cell growth and division. Mutations in the KRAS gene are frequently found in human cancers and can lead to uncontrolled cell growth.

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oncogenes

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

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

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MAPK

Mitogen-activated protein kinase

The MAPK pathway is a series of chemical reactions inside cells that transmits signals from the outside to the nucleus. This pathway plays a crucial role in regulating cell growth, differentiation, and survival.

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PI3K

Phosphoinositide 3-kinase

The PI3K pathway is another important signaling pathway that controls cell growth, metabolism, and survival. It often works in conjunction with the MAPK pathway.

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E3 ligases

Enzymes that tag proteins for degradation by the proteasome.

E3 ligases are proteins that play a critical role in regulating protein levels within cells. They recognize specific target proteins and attach a small molecule called ubiquitin to them, marking them for destruction.

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molecular glues

Small molecules that bind to proteins and promote protein-protein interactions.

Molecular glues are a novel class of drugs that aim to manipulate protein-protein interactions. They work by bringing together two proteins that normally wouldn't interact, leading to changes in cellular function.

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VHL

Von Hippel-Lindau tumor suppressor protein

VHL is a protein that normally helps to regulate cell growth and prevent the formation of tumors. Mutations in the VHL gene can lead to various types of cancer.

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G12 mutants

KRAS mutations in the G12 codon.

G12 mutants are a specific type of KRAS mutation that is often found in cancers. These mutations disrupt the normal function of the KRAS protein and contribute to uncontrolled cell growth.