RESEARCH: CANCER
FOLDING PROJECT #16494 PROFILE

This project studies RIPK2, a protein that plays a role in cancer. Researchers are using computer simulations to understand how three known inhibitors block RIPK2's ability to interact with another protein called XIAP. This could lead to better cancer treatments by optimizing these inhibitors.

Note: This TLDR is a simplication and may not be 100% accurate.

Kinases are a major target for a variety of cancer therapies, but their mechanism of action is relatively unknown at a detailed atomic level, preventing us from understanding and optimizing known inhibitors.

One example is the Serine/Threonine Kinase RIPK2.

RIPK2 inhibition is useful for cancer targeting as it prevents RIPK2 from binding a protein partner named XIAP.

In fact, there are already 3 known inhibitors that bind to RIPK2 and prevent RIPK2-XIAP binding! However, it remains difficult to optimize these ligands for clinical purposes because we do not understand how any of these three inhibitors actually act on RIPK2 to prevent XIAP binding behavior.

These four projects are simulating RIPK2 by itself and bound to each of the three inhibitors, with the hope that this will reveal a more detailed mechanism of how each inhibitor works to prevent XIAP binding.

As a bonus, this will help reveal how RIPK2 *binds* XIAP (also unknown)! In this set of projects we are studying the following systems: 16466 – RIPK2 16467 – RIPK2:CSLP43 inhibitor-bound complex 16468 – RIPK2:CSLP48 inhibitor-bound complex 16469 – RIPK2:GSK583 inhibitor-bound complex 16470 – RIPK2:WEHI-345 inhibitor-bound complex 16471 – RIPK2:BI inhibitor-bound complex 16488 – RIPK2:BI inhibitor-bound complex (alt configuration) 16489 – RIPK2:BI inhibitor-bound complex (alt configuration 2) 16490 – RIPK2:NVS inhibitor-bound complex 16491 – RIPK2 apo from the GSK bound structure 16492 – RIPK2 apo fro the BI bound structure 16493 – RIPK2 apo from a Gefitinib bound structure 16494 – RIPK2 apo from a Novartis-produced inhibitor 16495 – RIPK2:Gefitinib complex 16496 – RIPK2:Novartis inhibitor structure.

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Kinases

Enzymes that transfer phosphate groups.

Kinases are a type of enzyme that play a crucial role in various cellular processes by adding phosphate groups to other molecules. They are involved in signaling pathways, cell growth, and metabolism. In cancer, kinases are often overactive, contributing to uncontrolled cell proliferation.

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RIPK2

Receptor-interacting protein kinase 2

RIPK2 is a protein that plays a role in cell death and inflammation. It's been found to be involved in the development of certain cancers, making it a potential target for drug therapies.

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Inhibitors

Molecules that block or reduce the activity of enzymes.

Inhibitors are substances that can prevent or slow down chemical reactions. In medicine, inhibitors are used to target specific enzymes involved in disease processes.

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XIAP

X-linked inhibitor of apoptosis protein

XIAP is a protein that inhibits cell death (apoptosis). Its overexpression can contribute to cancer development by preventing the elimination of damaged cells.

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CSLP43

Cyclin-dependent kinase like protein 43

CSLP43 is a protein that interacts with RIPK2 and may play a role in regulating cell signaling.

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GSK583

GlaxoSmithKline compound 583

GSK583 is a drug candidate that has been shown to inhibit RIPK2 activity.

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WEHI-345

Walter and Eliza Hall Institute compound 345

WEHI-345 is a small molecule inhibitor of RIPK2 that has shown potential in preclinical cancer models.

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BI

Bristol Myers Squibb inhibitor

BI refers to a series of inhibitors developed by Bristol Myers Squibb that target RIPK2.

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Gefitinib

Epidermal growth factor receptor (EGFR) inhibitor

Gefitinib is a drug used to treat certain types of lung cancer by blocking the activity of EGFR.

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Novartis inhibitor

Inhibitor developed by Novartis

This refers to an inhibitor of RIPK2 being developed by the pharmaceutical company Novartis.