RESEARCH: CANCER
FOLDING PROJECT #16475 PROFILE

This project explores how small molecules block the growth of cancer cells by targeting a protein called Menin. Researchers are using computer simulations to understand how these molecules interact with Menin and how changes in Menin's structure affect this binding. The goal is to find ways to overcome resistance to treatment caused by mutations in Menin.

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 tumor suppressor protein involved in gene expression regulation.

Menin is a protein found in the nucleus of cells and plays a crucial role in regulating cell signaling and gene expression. It helps control which genes are turned on or off, impacting various cellular processes. In cancer treatment, Menin is a target because its malfunction can contribute to tumor growth. Targeting Menin with small molecules has shown promise in blocking tumor development.

Tumor

An abnormal mass of tissue that can be benign or malignant.

A tumor is an abnormal growth of cells in the body. It can be benign (non-cancerous) and grow slowly without spreading, or it can be malignant (cancerous), invading surrounding tissues and potentially spreading to other parts of the body.

Protein

Large biomolecules essential for various biological functions.

Proteins are complex molecules made up of chains of amino acids. They perform diverse functions in living organisms, including catalyzing biochemical reactions, transporting molecules, providing structural support, and regulating cell processes.

Small Molecule

A molecule with a low molecular weight that can interact with biological targets.

Small molecules are organic compounds with relatively low molecular weights. They are often used as drugs because they can bind to specific proteins in the body, altering their function and producing therapeutic effects.

Mutation

A permanent alteration in the DNA sequence.

Mutations are changes in the DNA sequence that can occur spontaneously or be induced by environmental factors. They can alter gene function and contribute to diseases like cancer.

Gene Expression

The process by which information encoded in DNA is used to synthesize RNA and proteins.

Gene expression is the intricate process by which the instructions stored in our DNA are converted into functional molecules like proteins. It involves two main steps: transcription (copying DNA into RNA) and translation (using RNA to build proteins). This process is tightly regulated and essential for all cellular functions.