RESEARCH: CANCER
FOLDING PROJECT #18011 PROFILE

This project investigates new cancer drugs called PROTACs that break down cancer-causing proteins instead of just blocking them. This approach is more effective against drug-resistant cancers and can target parts of proteins that regular drugs can't. Scientists use computer models to design these drugs and make the data publicly available.

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 gene that encodes a protein involved in chromatin remodeling.

SMARCA2 is a gene that provides instructions for making a protein crucial for regulating how DNA is packaged and accessed within cells. This process is vital for many cellular functions, including cell growth and division. In cancer, mutations or alterations in SMARCA2 can contribute to uncontrolled cell proliferation and tumor development.

BRD4

A gene that encodes a protein involved in regulating gene expression.

BRD4 is a gene that produces instructions for making a protein that acts as a 'switch' for controlling gene activity. It plays a role in various cellular processes, including cell growth, differentiation, and inflammation. In cancer, BRD4 can be overexpressed or abnormally activated, contributing to tumor development and progression.

Bcl

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

Bcl proteins are a group of molecules that act like gatekeepers controlling whether a cell lives or dies. In healthy cells, they maintain a balance between cell survival and programmed death. However, in cancer cells, Bcl proteins can become dysregulated, promoting resistance to cell death and contributing to tumor growth.

BTK

A protein involved in B-cell receptor signaling.

BTK is a protein essential for the proper functioning of B cells, a type of white blood cell involved in the immune response. In certain cancers affecting B cells, such as chronic lymphocytic leukemia (CLL), BTK becomes overactive, driving uncontrolled cell growth. Inhibiting BTK has become a targeted therapy approach for these cancers.

PROTACs

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs designed to degrade target proteins within cells. They function by recruiting an E3 ubiquitin ligase to bind to the desired protein, ultimately leading to its marking for destruction by cellular machinery. This approach offers advantages over traditional inhibitors by potentially achieving more potent and durable effects.

AMBER

A molecular simulation package used for studying biomolecular systems.

AMBER is a powerful computational tool widely used by researchers to simulate the behavior of molecules, including proteins and small drug-like compounds. It allows scientists to predict how molecules interact with each other, providing valuable insights for drug design and development.