RESEARCH: CANCER
FOLDING PROJECT #18003 PROFILE

This project is trying to find new cancer drugs that work even when tumors become resistant to existing treatments. It focuses on a new technology called PROTACs, which can destroy harmful proteins instead of just blocking them. Scientists are using computer models and experiments to design these drugs and make them more effective.

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 chromatin remodeling protein involved in gene regulation.

SMARCA2 is a protein that helps control how genes are turned on and off. It plays a role in many cellular processes, including DNA repair and cell growth. In cancer, SMARCA2 can be overexpressed or mutated, leading to uncontrolled cell division.

BRD4

Bromodomain containing protein 4, involved in gene transcription.

BRD4 is a protein that helps regulate gene expression by binding to specific DNA sequences. It plays a role in cell growth, differentiation, and inflammation. BRD4 is often overexpressed in cancer cells, contributing to their uncontrolled growth.

Bcl

B-cell lymphoma 2 family of proteins, involved in apoptosis.

Bcl is a group of proteins that play a crucial role in regulating cell death (apoptosis). Some Bcl proteins promote cell survival, while others trigger apoptosis. In cancer, Bcl proteins are often dysregulated, leading to resistance to cell death and promoting tumor growth.

BTK

Bruton's tyrosine kinase, involved in B cell signaling.

BTK is an enzyme that plays a key role in the signaling pathways of B cells, which are a type of white blood cell. BTK inhibitors are used to treat certain types of B cell cancers.

PROTAC

PROteolysis TArgeting Chimeras

PROTACs are a novel class of drugs that work by degrading target proteins instead of inhibiting them. They consist of two parts: a ligand that binds to the target protein and a ubiquitin ligase recruiter that tags the protein for degradation. This method offers several advantages over traditional inhibitors, including improved efficacy, selectivity, and the ability to target previously undruggable proteins.

AMBER

Assisted Model Building with Energy Refinement

AMBER is a widely used software package for simulating and analyzing biomolecular systems. It employs force fields to describe the interactions between atoms in molecules and uses algorithms to calculate their energies and trajectories over time. AMBER is commonly used in drug discovery to predict the binding affinity of ligands to target proteins.