RESEARCH: CANCER
FOLDING PROJECT #16474 PROFILE

This project explores how small molecules can block cancer growth by targeting a protein called Menin. Scientists will use computer simulations to understand how these molecules work and how mutations in Menin can make it harder for them to bind. This research could lead to new cancer treatments.

In cancer treatment it is common to target multiple different putative proteins, because multiple proteins can malfunction in tumors to drive cancer.

One such protein, particularly known to be important in endocrine gland tumors (the places where hormones are secreted), is Menin-1 (Menin).

Menin is a protein found in the nucleus protein and plays a key role in regulating cell-signaling and gene expression (which genes turn on and off).

While the explicit details of Menin's behavior are not known, targeting it's inhibition with small-molecules (ligands) has demonstrated promising potential in blocking tumor growth.

However, like with many disease, mutations within Menin can *also* counteract this ligand-binding behavior.

Therefore, it is not just important to study how Menin works, or how to target it with small molecules, but also how mutations impact Menin-Ligand interactions.

This set of projects seeks to answer the latter two questions - how do small molecules inhibit Menin and how do mutations within Menin alter small-molecule affinity.

In projects 16472 & 16473, we simulate Menin by itself and Menin bound to a known small molecule inhibitor that is shown to treat tumors in patients! Thanks to the powerhouse efforts at cataloguing cancer mutations at Memorial Sloan-Kettering, we also know of 3 mutations that impact the ability of Menin to bind this inhibitor.

Projects 16474–16483 simulate either a) each of these Menin mutants or b) Menin mutants bound to this inhibitor. Bonus: Some of these structures are being simulated with the help of the AlphaFold database!.

Menin

A protein found in the nucleus that regulates cell signaling and gene expression.

Menin is a crucial protein located in the cell's nucleus. It plays a vital role in controlling how cells communicate with each other and which genes are switched on or off. In certain cancers, particularly those affecting endocrine glands (hormone-producing organs), Menin malfunctions, contributing to tumor growth. Researchers are investigating ways to target Menin using drugs called small molecules to inhibit its activity and potentially stop tumor development.

Ligands

Small molecules that bind to specific proteins, often altering their function.

Ligands are small chemical compounds that can attach themselves to specific proteins within cells. This binding can either activate or inhibit the protein's activity. In drug development, ligands are crucial for creating medications that target specific disease pathways. For example, researchers are developing ligands that bind to Menin, a protein involved in cancer growth, with the goal of inhibiting its function and slowing tumor progression.

Mutations

Permanent changes in the DNA sequence.

Mutations are alterations in the genetic code (DNA) that can change how genes function. These changes can occur spontaneously or be induced by environmental factors. In cancer, mutations are common and contribute to the uncontrolled growth and spread of cells. Understanding how mutations affect proteins like Menin is essential for developing targeted therapies against specific types of cancer.

Small Molecules

Low-molecular-weight organic compounds used as drugs.

Small molecules are a diverse class of drug compounds characterized by their relatively small size. These molecules can interact with specific proteins within cells, modulating their activity and influencing biological processes. In oncology, small molecules are frequently used to target cancer-related proteins, such as Menin, aiming to inhibit tumor growth and progression.

AlphaFold

A deep learning algorithm for predicting protein structures.

AlphaFold is a powerful artificial intelligence (AI) system developed by DeepMind that excels at predicting the three-dimensional structures of proteins. Proteins are essential biological molecules with diverse functions. Knowing their shapes helps researchers understand how they work and develop new drugs or therapies. AlphaFold has revolutionized protein structure prediction, accelerating research in various fields, including cancer biology.