RESEARCH: CANCER
FOLDING PROJECT #18704 PROFILE

Von Hippel-Lindau (VHL) syndrome causes tumors by affecting a gene that regulates cell growth. This project uses computer simulations to design drugs called PROTACs that can target and break down the problematic protein, offering a new way to treat this rare disease.

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) syndrome

Von Hippel-Lindau syndrome (VHL) is a rare genetic disorder.

VHL syndrome is an inherited disease that causes the growth of tumors and cysts in various parts of the body. These growths can be noncancerous, but some may develop into cancer, particularly those affecting the kidneys and pancreas. VHL occurs due to mutations in the VHL gene, leading to abnormal protein function and contributing to tumor development.

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tumor

An abnormal growth of tissue in the body.

A tumor is an abnormal mass of cells that develops when cells grow and divide uncontrollably. Tumors can be benign (noncancerous) or malignant (cancerous). Benign tumors usually don't spread to other parts of the body, while malignant tumors can invade surrounding tissues and spread to distant organs.

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cyst

A closed sac filled with fluid or semi-solid material.

A cyst is a sac-like structure found in the body that contains a fluid or semi-solid substance. Cysts can develop in various organs and tissues. Some cysts are harmless, while others may cause discomfort or complications.

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mutation

A permanent alteration in the DNA sequence.

A mutation is a change in the genetic code (DNA) that can alter the instructions for building and maintaining an organism. Mutations can be caused by various factors like errors during DNA replication, exposure to radiation or chemicals, or inherited from parents.

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gene

A segment of DNA that contains instructions for building a specific protein.

A gene is a basic unit of heredity that carries the instructions for making proteins. Proteins are essential molecules that carry out various functions in the body. Genes are located on chromosomes and passed down from parents to offspring.

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protein

A large molecule composed of amino acids.

Proteins are complex molecules that play crucial roles in virtually all biological processes. They have diverse functions, including catalyzing reactions, transporting molecules, providing structural support, and regulating cellular activities.

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E3 ligase

An enzyme that facilitates the attachment of ubiquitin to a target protein.

E3 ligases are enzymes involved in a cellular process called ubiquitination. They play a key role in regulating protein degradation by attaching small protein molecules called ubiquitin to specific target proteins.

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ubiquitin

A small protein that tags other proteins for degradation.

Ubiquitin is a small protein molecule that acts as a cellular signal. It attaches to other proteins, marking them for destruction by cellular machinery.

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hypoxia

A condition in which the body or a region of the body is deprived of adequate oxygen supply.

Hypoxia refers to a state where there is insufficient oxygen available to meet the body's needs. It can occur due to various factors like lung diseases, heart problems, high altitude, or carbon monoxide poisoning.

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PROTAC

Proteolysis-targeting chimera

PROTACs are a new class of drugs that work by tagging proteins for destruction. They consist of two parts: a ligand that binds to the target protein and a moiety that recruits an E3 ligase.