RESEARCH: CANCER
FOLDING PROJECT #18005 PROFILE

This project aims to find new cancer drugs that work even when tumors become resistant. They're using a special technology called PROTACs which breaks down harmful proteins instead of just blocking them. This approach is more effective and can target parts of proteins beyond just their active sites. The researchers use computer models to understand how these drugs work and are making their data public.

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/.

SMARCA2

A protein that regulates gene expression.

SMARCA2 is a protein involved in controlling how genes are turned on and off. It plays a role in various cellular processes and has been implicated in cancer development.

BRD4

Bromodomain-containing protein 4.

BRD4 is a protein that binds to specific DNA sequences and plays a role in regulating gene expression. It has been identified as a potential target for cancer therapy.

Bcl

B-cell lymphoma

Bcl refers to a group of proteins that regulate cell death. They are involved in various cellular processes and have been implicated in cancer development.

BTK

Bruton's tyrosine kinase

BTK is an enzyme involved in immune cell signaling. It plays a role in B-cell development and activation and has been targeted for cancer therapy.

PROTAC

Proteolysis TArgeting Chimeras

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

AMBER

Assisted Model Building with Energy Refinement.

AMBER is a widely used software package for simulating molecular interactions. It is commonly used in drug discovery to predict the binding affinity of molecules to their targets.