RESEARCH: CANCER
FOLDING PROJECT #18701 PROFILE

Von Hippel-Lindau (VHL) syndrome causes tumors by messing up a protein called HIF. This project is using computer simulations to design PROTAC molecules that can bind to both VHL and HIF, helping the body break down excess HIF and control tumor growth.

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

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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Tumors

Abnormal growths of tissue

Tumors are abnormal masses of cells that can be benign (non-cancerous) or malignant (cancerous). They can develop in various parts of the body and often require medical attention.

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Cysts

Closed sacs filled with fluid

Cysts are non-cancerous, fluid-filled sacs that can develop in various organs and tissues. They often grow slowly and may not cause symptoms unless they become large or press on surrounding structures.

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Kidney

Organ responsible for filtering waste from the blood

The kidneys are bean-shaped organs that filter waste products from the blood and produce urine. They also regulate blood pressure, electrolyte balance, and red blood cell production.

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Pancreas

Organ that produces insulin and digestive enzymes

The pancreas is an organ with two main functions: it produces insulin, a hormone that regulates blood sugar levels, and digestive enzymes that break down food in the small intestine.

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VHL gene

Gene responsible for producing the VHL protein

The VHL gene provides instructions for making the VHL protein, which plays a role in regulating cell growth and preventing tumors. Mutations in this gene can lead to Von Hippel-Lindau syndrome.

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E3 ligase

Enzyme that tags proteins for degradation

E3 ligases are enzymes that play a crucial role in protein degradation by tagging them with ubiquitin molecules. This process marks proteins for destruction by cellular machinery.

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Ubiquitinate

Attach ubiquitin molecules to proteins

Ubiquitination is a process where ubiquitin molecules are attached to proteins. This can serve various functions, including marking proteins for degradation, regulating protein activity, or influencing protein localization.

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Hypoxia-inducible factor (HIF)

Hypoxia-inducible factor

HIF is a protein complex that plays a critical role in cellular responses to low oxygen levels (hypoxia). It regulates the expression of genes involved in adapting to oxygen deprivation.

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PROs

Proteins of Interest

PROs are specific proteins being studied in research for their roles in disease or as potential drug targets.

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PROTeomics

Study of proteins

Proteomics is the large-scale study of proteins, including their structure, function, interactions, and changes in response to various stimuli.

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PROTein microarrays

Arrays for detecting proteins

Protein microarrays are high-throughput tools used to detect and quantify thousands of proteins simultaneously. They play a crucial role in proteomics research and drug discovery.

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PROTein interactions

How proteins interact with each other

Protein interactions are essential for various cellular processes. Proteins can interact with each other to form complexes, carry out enzymatic reactions, regulate gene expression, and signal transduction.

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PROTein engineering

Modifying proteins for specific purposes

Protein engineering involves modifying the structure or function of proteins to create novel molecules with desired properties. It has applications in developing therapeutics, diagnostic tools, and industrial enzymes.

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PROdrugs

Inactive drug precursors that become active in the body

Prodrugs are inactive drug molecules that are designed to be converted into their active form within the body. This can improve drug delivery, target specificity, and reduce side effects.

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PROtein arrays

Arrays for detecting proteins

Protein arrays are high-throughput tools used to detect and quantify thousands of proteins simultaneously. They play a crucial role in proteomics research and drug discovery.

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PROtein microarrays

Arrays for detecting proteins

Protein microarrays are high-throughput tools used to detect and quantify thousands of proteins simultaneously. They play a crucial role in proteomics research and drug discovery.