RESEARCH: CANCER
FOLDING PROJECT #18025 PROFILE

This project explores new cancer drugs that work by destroying target proteins instead of blocking them. This method could overcome drug resistance and affect more parts of a protein than traditional drugs. Researchers use computer simulations to understand how these drugs work and make better ones.

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.

SMARCA2

A protein involved in chromatin remodeling.

SMARCA2 is a gene that codes for a protein essential for regulating DNA accessibility. Alterations in SMARCA2 can contribute to cancer development by affecting how genes are expressed.

BRD4

A protein involved in gene regulation and cell proliferation.

BRD4 is a gene that codes for a protein playing a crucial role in regulating gene expression. Its overexpression can contribute to cancer growth by promoting uncontrolled cell division.

Bcl

A family of proteins involved in apoptosis (cell death).

Bcl refers to a group of genes that produce proteins influencing programmed cell death. Some Bcl proteins promote cell survival, while others trigger apoptosis, and their balance is crucial for normal cellular function.

BTK

Bruton's tyrosine kinase

BTK is an enzyme crucial for immune cell signaling. Its dysregulation can lead to certain types of cancers, making it a target for therapy.

PROTACs

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that induce protein degradation by hijacking the cell's natural protein recycling system. They offer a promising alternative to traditional inhibitors for treating various diseases.

AMBER

A software package for molecular simulations.

AMBER is a widely used computer program that simulates the behavior of molecules at the atomic level. It's essential for understanding how drugs interact with their targets and predicting their effectiveness.