RESEARCH: CANCER
FOLDING PROJECT #18022 PROFILE

The project investigates new anti-cancer drugs called PROTACs that break down cancer-causing proteins instead of just blocking them. This approach is more effective against drug-resistant cancers and can target a wider range of protein functions. Researchers use computer simulations to design PROTACs and are making their data publicly available.

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

This project investigates anti-cancer drugs that might overcome drug resistance.

The targets considered are major oncogenes like SMARCA2, BRD4, Bcl and BTK.

Drug-resistance is a major and unavoidable problem and presently only 20–25NULLof all protein targets are studied.

Moreover, the focus of current explorations of targets are their enzymatic functions, while ignoring the functions from their scaffold moiety.

Roivant's drug discovery choose to focus on a promising new technology, PROteolysis TArgeting Chimeras (PROTACs) which regulates protein function by degrading target proteins instead of inhibiting them.

This method provided more sensitivity to drug-resistant targets, better selectivity, and a greater chance to affect the nonenzymatic functions of targeted proteins.

Roivant is leading in the general paradigm shift that looks at the kinetics of reactions instead of binding thermodynamics for its PROTACs drug discovery.

Specifically, by understanding the balance between changes of entropy and enthalpy and the competition between a ligand and water molecules in molecular binding, which is known to be crucial for smart drug discovery.

Experiments provide measurements, however, computational methods provide information about binding/unbinding processes that allows for a complete picture of molecular recognition not directly available from experiments.

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

The experimental data is used to guide and improve the predictive, modeling tools for PROTAC drug discovery in iterative manner.

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. This is a project run by Roivant Sciences (formerly Silicon Therapeutics) as was officially announced in this press release: https://foldingathome.org/2021/04/20/maximizing-the-impact-of-foldinghome-by-engaging-industry-collaborators/ All data is being made publicly available in real time at https://console.cloud.google.com/storage/browser/stxfah-bucket.

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oncogenes

Genes that can cause cancer to develop.

Oncogenes are genes that have the potential to cause cancer. When they become mutated or overactive, they can promote uncontrolled cell growth and division, leading to tumor formation.

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SMARCA2

SWI/SNF-related matrix-associated, actin-dependent regulator of chromatin, subfamily A member 2

SMARCA2 is a protein that plays a role in regulating gene expression. It is involved in chromatin remodeling, which is the process of altering the structure of DNA and its associated proteins to control gene activity. Mutations in SMARCA2 have been linked to various cancers.

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BRD4

Bromodomain-containing protein 4

BRD4 is a protein that binds to acetylated histones, which are proteins associated with DNA. BRD4 plays a role in gene regulation and has been implicated in the development of various cancers.

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Bcl

B-cell lymphoma 2 protein family

Bcl proteins are a family of proteins that play a role in regulating apoptosis, or programmed cell death. Some Bcl proteins promote cell survival, while others induce apoptosis.

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BTK

Bruton's tyrosine kinase

BTK is a protein that plays a crucial role in the development and function of B cells, a type of white blood cell involved in the immune response.

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PROTACs

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that work by targeting proteins for degradation. They consist of two parts: a ligand that binds to the target protein and a recruiter that binds to an E3 ligase, which is responsible for tagging proteins for degradation.

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AMBER

Assisted Model Building with Energy Refinement

AMBER is a widely used software package for molecular modeling and simulations. It is used to study the structure, dynamics, and interactions of biomolecules.