By Marty Trieschmann
April 22, 2025 | Molecular Cell publishes UAMS comprehensive structural biology study of MCL-1:BAK complex found in most cancers
A research team led by UAMS Winthrop P. Rockefeller Cancer Institute scientist, Tudor Moldoveanu, Ph.D., has uncovered novel insights into one of the body’s most fundamental processes impacting the development of cancer. Known as apoptosis, the research on the process of programmed cell death was published April 4 in the high-impact journal Molecular Cell.
“At a high level, our research tackles a central mechanism of cell death known as apoptosis,” said Moldoveanu, an associate professor in the UAMS College of Medicine Department of Biochemistry and Molecular Biology and co-leader of the Cancer Institute’s Cancer Therapeutics Research Program.
“Apoptosis is a fundamental biological process that supports our health,” he said. “Our bodies need to get rid of cells that are too old or damaged to work properly. If those cells keep hanging around, they can harm us and lead to cancer and other conditions.”
Moldoveanu’s study focuses on the protein complex MCL-1:BAK which blocks apoptosis when formed and is a common target for drug makers.
“There are four other known proteins similar to MCL-1 that inhibit apoptotic cell death that we know of, and MCL-1 is one of the worst that shows up in a lot of cancers,” Moldoveanu said. “It’s one of the most upregulated proteins in cancer that makes it harder for cell death to happen and is a proven recipe for growing tumors in cancer.”
In multiple myeloma, MCL-1 is responsible for more than 40% of new cases and more than 70% of relapsed, refractory cases. BAK is a pro-death protein that initiates apoptosis when activated by cancer therapies and often interacts with MCL-1 blocking its pro-apoptotic role.
For the first time, drug makers now have an atomic level view of the MCL-1:BAK protein complex. Moldoveanu’s team used an integrated structural biology approach with nuclear magnetic resonance (NMR) spectroscopy, cryo-electron microscopy (cryo-EM) and X-ray crystallography, to provide the most detailed characterization of the molecular structure of the complex to date.
After testing select highly potent drugs designed to inhibit MCL-1 in a reconstituted MCL-1:BAK complex in the lab, the results surprised even Moldoveanu.
“One of the most surprising findings is that MCL-1 inhibitors are not very good in neutralizing the MCL-1:BAK complex, requiring high doses to initiate cell death. Our study underscores the need to design superior MCL-1 inhibitors.”
Moldoveanu is the lead author of the study between his lab in the UAMS Department of Biochemistry and Molecular Biology and collaborators at St. Jude Children’s Research Hospital, the University of Chicago, the University of Arkansas in Fayetteville and École Polytechnique Fédérale de Lausanne.
“Among the cancer therapies available to us, we have very few inhibitors to regulate cell death in patients with cancer,” Moldoveanu said.
“The problem is that current inhibitors targeting MCL-1 also impact organs and tissues, such the heart and cells that line the blood vessels,” he added. “These cells are highly susceptible to toxicity from cancer chemotherapy in general, so the issue is how to administer MCL-1 inhibitors to initiate cell death safely and in a more targeted way that doesn’t go everywhere in the body.
“Now that we have a better view of how this complex looks and forms and that these drugs are not as effective as we imagined, we can move forward with designing future therapies to have better potency and bioavailability in neutralizing this pathway,” said Moldoveanu.
