RESEARCH: CANCER
FOLDING PROJECT #18010 PROFILE

This project is trying to find new cancer drugs that can beat drug resistance. Instead of just blocking the bad proteins, these drugs work by breaking them down. This makes them better at fighting even resistant cancers and lets them target all parts of a protein, not just its active site.

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/.

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Oncogenes

Genes that have the potential to cause cancer.

Oncogenes are genes that can promote the uncontrolled growth and spread of cells, leading to the development of cancer. They arise from mutations in normal genes called proto-oncogenes.

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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 and DNA repair. Mutations in this gene have been linked to cancer.

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BRD4

Bromodomain Containing 4

BRD4 is a protein that interacts with DNA and regulates gene expression. It plays a role in cancer cell growth and survival.

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Bcl

B-cell lymphoma 2 family of proteins

The Bcl protein family plays a role in regulating cell death (apoptosis). Overexpression of some Bcl proteins can promote cancer cell survival.

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BTK

Bruton's tyrosine kinase

BTK is an enzyme that plays a role in immune cell signaling. It is often overactive in certain types of cancer.

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PROTACs

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that target proteins for degradation. They work by recruiting an E3 ligase to bind to the target protein, marking it for destruction.

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Protein-Ligand Interactions

The binding of a protein to a small molecule ligand.

Protein-ligand interactions are crucial for many biological processes. In drug discovery, understanding these interactions helps design drugs that bind to specific proteins and exert their therapeutic effects.

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AMBER Force Fields

A set of parameters used in molecular dynamics simulations to describe the interactions between atoms.

AMBER force fields are mathematical models that represent the potential energy of molecules. They are widely used in computational drug discovery to simulate protein-ligand interactions and predict drug binding affinities.