New anti-cancer ‘degrader’ targets protein essential to infant leukemia

GRAND RAPIDS, Mich. (Aug. 29, 2024) — Scientists at Van Andel Institute and Icahn School of Medicine at Mount Sinai have developed a potent anti-cancer compound that inhibits cancer cell growth in a tough-to-treat type of infant leukemia.  

The compound, MS-41, targets and destroys ENL, a protein that is essential to the progression of MLL-rearranged leukemia. Without ENL, leukemia cells lose the ability to proliferate and spread.

“Up to 80% of acute leukemias in infants are linked to problems with the MLL gene, yet there are few effective treatments for MLL-rearranged leukemias,” said VAI Professor Hong Wen, Ph.D., co-corresponding author of a study describing the findings. “MS-41 is a new, experimental compound that effectively targets and degrades a central survival mechanism in leukemia cells. Our early results are promising, and we’re excited to continue developing MS-41 as a potential leukemia treatment.”

MS-41 belongs to a family of cancer-fighting compounds called PROTAC degraders, which are an increasingly popular approach to cancer drug development. Unlike traditional small-molecule inhibitors, PROTAC degraders completely remove their target proteins, enabling them to deliver robust therapeutic effects at low doses with fewer side-effects. PROTAC degraders also often require less frequent treatment than other currently available cancer medications.

The findings, published in the journal Science Advances, also reveal that MS-41 did not harm healthy cells when tested in mouse models. Such compounds are desirable as medications because they are less likely to cause side effects.

Moving forward, Wen and her colleagues will investigate MS-41 in additional models to assess if it is applicable in other types of ENL-related acute leukemias and cancer types such as Wilms tumor. 

Jian Jin, Ph.D., of Icahn School of Medicine at Mount Sinai is co-corresponding author. Zhaoyu Xue, Ph.D., and Hongwen Xuan, Ph.D., of VAI, and Lihuai Qin, Ph.D., and Kaixiu Luo, Ph.D., of Icahn School of Medicine at Mount Sinai, are co-first authors. Other authors include Mengying Huang, Ph.D., Yangzhou Su, Longxia Xu, Ph.D., Josiah Harsh, and Xiaobing Shi, Ph.D., of VAI; Brandon Dale, Ph.D., and H. Ümit Kaniskan, Ph.D., of Icahn School of Medicine at Mount Sinai; and Ling Xie, Ph.D., Xian Chen, Ph.D., of University of North Carolina at Chapel Hill.

Van Andel Institute’s High-Performance Cluster and Cloud Computing and the following Van Andel Institute Core Technologies and Services also contributed to this work: Genomics Core (RRID:SCR_022913), Flow Cytometry Core (RRID:SCR_022685), Vivarium Core (RRID:SCR_023211), Pathology and Biorepository Core (RRID:SCR_022912) and Bioinformatics and Biostatistics Core (RRID:SCR_024762).

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award no. R01CA260666 (Jin and Wen).

Wen is a Career Development Award Scholar of the Leukemia & Lymphoma Society (award no. 1387-23). Wen also is supported by the National Cancer Institute of the National Institutes of Health under award no. R01CA255506. Shi is supported by the National Cancer Institute of the National Institutes of Health under award no. R01CA268440. Chen is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health award no. R41DK13305, the National Institute on Aging of the National Institutes of Health under award no. R21AG071229 and the National Institutes of General Medical Sciences of the National Institutes of Health under award no. R01GM133107.

This work used the NMR Spectrometer Systems at Mount Sinai acquired with funding from the National Institutes of Health under Shared Instrument award nos. 1S10OD025132 and 1S10OD028504.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.  

###

ABOUT VAN ANDEL INSTITUTE
Van Andel Institute (VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to more than 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K–12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology. Learn more at vai.org.