RESEARCH: CANCER
FOLDING PROJECT #18016 PROFILE

This project looks at new drugs to fight cancer that are resistant to other treatments. Instead of blocking cancer proteins, these drugs destroy them. This approach is more effective and can target parts of cancer proteins that regular drugs can't reach. The project uses computer models and experiments to design these new drugs.

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

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's involved in processes like chromatin remodeling and DNA repair. In cancer, SMARCA2 mutations can contribute to tumor growth and spread.

BRD4

Bromodomain-containing protein 4

BRD4 is a protein that reads signals on DNA and regulates gene expression. It's involved in processes like cell growth and division. In cancer, BRD4 can be overactive, promoting tumor growth. Drugs targeting BRD4 are being developed to treat various cancers.

Bcl

B-cell lymphoma 2 family of proteins

The Bcl family of proteins plays a critical role in cell death (apoptosis). Some members promote cell survival, while others trigger apoptosis. In cancer, Bcl proteins can be overexpressed or mutated, preventing cells from dying and contributing to tumor growth.

BTK

Bruton's tyrosine kinase

BTK is an enzyme involved in signaling pathways important for immune cell function. In certain types of blood cancers like chronic lymphocytic leukemia (CLL), BTK is often overactive. Drugs that inhibit BTK are used to treat these cancers.

PROTAC

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that work by hijacking the cell's own protein degradation machinery. They target specific proteins and bring them to the proteasome, a cellular complex that breaks down proteins. This approach offers advantages over traditional inhibitors by potentially overcoming drug resistance and targeting non-enzymatic functions.

AMBER

Assisted Model Building with Energy Refinement

AMBER is a popular software package used in computational chemistry for molecular modeling and simulations. It's widely employed in drug discovery to study protein-ligand interactions, predict binding affinities, and design new drugs.