A team of scientists from the University of Michigan Rogel Cancer Center has developed the first drug-like compounds to inhibit a key family of enzymes whose malfunction is associated with several types of cancer, including an aggressive form of childhood leukemia.
The enzymes — known as the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases — have long been an attractive drug target, but efforts to attack them have previously proved elusive because the shape of the binding sites in these enzymes makes it difficult for drug-like molecules to bind to it.
The research team — led by Tomasz Cierpicki, PhD, and Jolanta Grembecka, PhD — used a variety of techniques including X-ray crystallography and nuclear magnetic resonance to develop first-in-class inhibitors of a key protein known as NSD1, according to findings published in Nature Chemical Biology.
The team’s lead compound — known as BT5 — showed promising activity in leukemia cells with the NUP98-NSD1 chromosomal translocation that is seen in a subset of pediatric leukemia patients.
“Our study, which was years in the making, demonstrates that targeting this key enzyme with small-molecule inhibitors is a feasible approach,” says Cierpicki, an associate professor of biophysics and pathology at U-M. “These findings will facilitate the development of the next generation of potent and selective inhibitors of these enzymes, which are overexpressed, mutated or undergo translocations in several types of cancer.”
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This story was written by Ian Demsky and originally appeared in the Michigan Medicine Health Lab Blog on 8/31/2020.
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Breast team reviewing a patient's slide. (From left to right) Ghassan Allo, Fellow; Laura Walters, Clinical Lecturer; Celina Kleer, Professor. See Article 2014Department Chair |
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Dr. Sriram Venneti, MD, PhD and Postdoctoral Fellow, Chan Chung, PhD investigate pediatric brain cancer. See Article 2017Department Chair |
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Director of the Neuropathology Fellowship, Dr. Sandra Camelo-Piragua serves on the Patient and Family Advisory Council. 2018Department Chair |
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INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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Residents Ashley Bradt (left) and William Perry work at a multi-headed scope in our new facility. 2019Department Chair |
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Dr. Kristine Konopka (right) instructing residents while using a multi-headed microscope. 2020Department Chair |
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Patient specimens poised for COVID-19 PCR testing. 2021Department Chair |
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Dr. Pantanowitz demonstrates using machine learning in analyzing slides. 2022Department Chair |
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(Left to Right) Drs. Angela Wu, Laura Lamps, and Maria Westerhoff. 2023Department Chair |
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INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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Illustration representing the various machines and processing used within our labs. 2024Department Chair |
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MLabs, established in 1985, functions as a portal to provide pathologists, hospitals. and other reference laboratories access to the faculty, staff and laboratories of the University of Michigan Health System’s Department of Pathology. MLabs is a recognized leader for advanced molecular diagnostic testing, helpful consultants and exceptional customer service.