Unique approach unlocks opportunity for previously undruggable cancerous targets to be discovered
INDIANAPOLIS—Researchers in the Department of Pathology and Laboratory Medicine at Indiana University School of Medicine have discovered a novel anti-cancer drug, using a unique approach that has allowed them to target previously undruggable cancerous proteins. When traditional drug discovery approaches failed, Anita Bellail, PhD, Chunhai Charlie Hao, MD, PhD, and their team developed a cancer cell-based screening to identify a lead compound known as HB007, which slowed cancer growth in models. Their findings were published this month in Science Translational Medicine.
“All proteins go through a life cycle from gene transcription to protein degradation,” said Bellail, the lead author who is an assistant professor of pathology and laboratory medicine at IU School of Medicine. “The cancerous proteins are highly expressed in part due to the blockage of degradation. Targeted protein degraders such as HB007 can release the blockage and send the proteins to the trash can.”
In the past, researchers have searched for compounds known as inhibitors to directly bind to and inhibit cancerous proteins, but the vast majority of proteins lack binding pockets. The next generation of drugs that Bellail, Hao and team are working to identify are small molecule degraders that target the protein degradation pathway for the destruction of cancerous proteins and shutdown of cancer growth.
Eighty percent of proteins in the human body are currently undruggable. The team led by Bellail and Hao, who are members of the IU Melvin and Bren Simon Comprehensive Cancer Center, designed and utilized a cancer cell-based drug screening process to identify the first small-molecule degraders of a cancerous protein called SUMO1, which was previously considered undruggable. The team has also discovered the novel CAPRIN1-CUL1 ubiquitin ligase that compound binds to and leads to SUMO1 recruitment to the ligase for destruction.
“We believe we are the first ones to report the step-by-step process of how to find the small molecule degraders of undruggable proteins,” said Hao, a senior author who is the Bicentennial Professor of Pathology and Laboratory Medicine and Neurological Surgery at IU School of Medicine and a member of the Vera Bradley Foundation Center for Breast Cancer Research at the cancer center. “This will generate a strategy that can help researchers find small molecule degraders as novel drugs. Since the degraders can destroy the proteins, the dose can be much lower, so efficacy is also much better.”
Bellail, Hao and colleagues tested their theory by observing patient-derived brain, breast, colon and lung cancers in animal models. Their approach suppressed the cancers and increased the survival of the animals. This approach may be useful for identifying other small-molecule degraders of cancerous proteins as the next generation of anticancer drugs.
Bellail and Hao came to IU School of Medicine in 2018 with the goal of building up novel drug discovery programs.
This work was supported in part by the Pathology Bicentennial Chair endowment and start-up fund, the Indiana University School of Medicine Physician Scientist Initiative funded by Lilly Endowment Inc., IU Simon Comprehensive Cancer Center’s 100 Voices of Hope program, the Vera Bradley Foundation for Breast Cancer Scholar fund, and National Institutes of Health grants R01CA203893 and R43CA224461.
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