RESEARCH: CANCER
FOLDING PROJECT #18703 PROFILE

VHL syndrome causes tumors by affecting a protein called HIF. This project uses computer simulations to design PROTAC molecules that can target and break down HIF, potentially treating VHL syndrome. By testing different molecule designs virtually, researchers can narrow down options for real-world experiments.

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

Von Hippel-Lindau (VHL) syndrome is a rare disease that causes tumors and cysts to develop and grow in the body.

These tumors usually are non-cancerous, but some, especially tumors that develop in the kidney and pancreas, may become cancerous.

VHL syndrome is caused by a mutation in the VHL gene, which decreases the VHL protein’s ability to act as an E3 ligase and ubiquitinate the α subunit of hypoxia-inducible factor (HIF), which decreases proteolysis of HIF proteins.

The elevated HIF levels are responsible for the hypervascularization in renal cell carcinoma associated with the VHL syndrome disease state.

This project investigates the design of heterobifunctional molecules, also known as PROteolysis TArgeting Chimeras (PROTACs), which can bind both the VHL and HIF2α and help regulate the degradation of HIF2α.

Experimental measurements can provide insights to the challenge of PROTAC optimization, but the design space is too large to test every potential molecule design.

Therefore, molecular dynamic simulations will be run on potential ligand candidates to reduce the amount of possible PROTAC hits and reduce the experiments necessary for validation.

Initially the warhead domain, the PROTAC’s binding domain to HIF2α, will be developed by running simulations using various different structures already bound to the protein and determining the stability of the bound state for each potential structure.

Then the linker region, the structure that connects the two binding domains, of the PROTAC will be developed by running simulations to determine the ternary structure for the VHL-PROTAC- HIF2α complex.

All the computed values of kon, koff, ΔH, ΔS, and ΔG use AMBER force fields for Protein-Protein and Protein-Ligand's interactions.

Roivant is using published PROTAC-bound ternary complexes, plus some data generated internally for the F@h projects, and all simulation data is being made publicly available.

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Von Hippel-Lindau (VHL)

Von Hippel-Lindau disease

A rare genetic disorder causing tumors and cysts in various organs. It's caused by a mutation in the VHL gene, affecting tumor suppression.

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VHL Gene

A gene that codes for a protein involved in regulating cell growth and preventing tumor formation.

The VHL gene produces a protein that controls cell division. Mutations in this gene can lead to the development of tumors.

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E3 ligase

An enzyme that attaches ubiquitin to target proteins, marking them for degradation.

E3 ligases are essential for breaking down damaged or unwanted proteins in the cell. They tag proteins with ubiquitin, signaling their destruction.

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Hypoxia-inducible factor (HIF)

A transcription factor that regulates gene expression in response to low oxygen levels.

HIF proteins activate genes needed for survival during low oxygen conditions. Their activity is tightly regulated.

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Renal Cell Carcinoma

A type of cancer that originates in the cells lining the renal tubules (kidneys).

Renal cell carcinoma is a common type of kidney cancer. Its development can be influenced by genetic factors and environmental exposures.

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PROteolysis TArgeting Chimeras (PROTACs)

Small molecules designed to degrade specific target proteins by recruiting the proteasome.

PROTACs are a novel drug strategy that aim to destroy disease-causing proteins. They work by hijacking the cell's natural protein degradation machinery.

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Molecular Dynamic Simulations

Computer simulations that model the movement and interactions of atoms and molecules over time.

Molecular dynamic simulations help researchers understand how proteins interact with each other and with drugs. They are used to predict protein structures and optimize drug design.

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AMBER Force Fields

Mathematical equations that describe the interactions between atoms in a molecule.

AMBER force fields are used in molecular simulations to accurately represent the behavior of proteins and other biomolecules.