"In essence, MALT1 turns off the brakes and presses the gas pedal to accelerate cell growth and survival in this aggressive cancer," Dr. Melnick says.
In this study, the researchers developed an activated form of MALT1 in the test tube that allowed them to study the structure of the molecule, and search for small molecule agents to shut it down. The key insights enabling this technical feat were achieved by co-lead investigator Dr. Hao Wu, an expert in biochemistry and structural biology and a former faculty member at Weill Cornell who is now at Harvard Medical School.
The researchers screened libraries of chemicals until they found one that tightly bonded to MALT1, preventing it from cutting other proteins. The agent, MI-2, also inactivated MALT1 in human samples of ABC-DLBCL, according to researchers.
When they tested the agent in mice, the research team found it stopped cancer growth without toxicity in normal tissues -- a trait Dr. Melnick says is due to the fact that MALT1 is not required for biological processes essential for life.
If tested successfully in human clinical trials, MI-2 could have benefits for other diseases, including MALT1 lymphoma, a lower-grade type of lymphoma. It could also possibly play a role in a variety of inflammatory and autoimmune disorders.
"MALT1 is a bona fide therapeutic target, and with the discovery of MI-2 we have provided a lead compound that forms the basis of a new class of therapeutic agents," says Dr. Melnick.
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New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College