RESEARCH: CANCER
FOLDING PROJECT #18004 PROFILE

This project looks at new cancer drugs called PROTACs that destroy cancer-causing proteins instead of just blocking them. This method could help overcome drug resistance, which is a big problem in cancer treatment. The project uses computer modeling to understand how these drugs work and improve their design.

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 involved in chromatin remodeling.

SMARCA2 is a gene that produces a protein important for controlling how tightly DNA is packaged. This packaging affects how genes are turned on or off, playing a role in cell growth and development.

BRD4

A protein involved in gene regulation.

BRD4 is a protein that helps control which genes are active in a cell. It plays a role in various cellular processes, including cell growth, division, and immune responses.

Bcl

A family of proteins involved in cell survival and death.

Bcl refers to a group of proteins that regulate programmed cell death (apoptosis). Some Bcl proteins promote cell survival, while others trigger cell death. They are crucial for maintaining healthy cell populations.

BTK

A protein involved in immune cell signaling.

BTK is a protein that plays a vital role in the activation and function of certain immune cells. It's involved in transmitting signals that lead to an immune response against pathogens.

PROTAC

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that work by degrading target proteins. They consist of two parts: a ligand that binds to the protein of interest and a recruiter molecule that tags it for destruction.

AMBER

A software package for molecular dynamics simulations.

AMBER is a widely used computer program that simulates the movement and interactions of atoms in molecules. It's essential for understanding how drugs interact with their targets.