Certain subtypes of blood cancers such as acute leukemias rely on multiple mechanisms to support the growth of aggressive cancer cells. Notably, these mechanisms include those driven by EZH2, a chromatin modulating enzyme, and cMyc, an important carcinogenic factor. UNC researchers are now showing that these two factors can directly associate with each other, modulating cancer cell-specific gene expression programs.

To develop pharmacological means to target both EZH2 and cMyc, they teamed up with chemical biologists from the Icahn School of Medicine at Mount Sinai and designed a new small molecule, MS177, based on PROTAC (proteolysis-targeting chimera). MS177 targets both EZH2 and cMyc and thus inhibits cancer growth.

Their findings are published online in Natural Cell Biology.

“EZH2 plays a very important role during cancer progression and is a known target for drug development,” said Greg Wang, PhD, associate professor of biochemistry, biophysics, and pharmacology at UNC Lineberger in the School of UNC Medicine and co-lead author of this article. research paper. “We are amazed by the effectiveness of the small molecule PROTAC in simultaneously targeting EZH2 and cMyc in cancer cells.”

They found that EZH2 has two different binding patterns on chromatin in acute leukemia cells, triggering two distinct gene regulatory programs. On the one hand, EZH2 forms a canonical protein complex called PRC2, leading to gene repression in a set of genomic regions; on the other hand, EZH2 interacts with cMyc to activate gene expression at genomic sites distinct from the previous ones. “This explains why current small molecule inhibitors of EZH2 cannot completely block EZH2. PROTAC fills this gap,” said Jun Wang, PhD, postdoctoral researcher at UNC Lineberger and co-first author of the work.

MS177 has a targeted effect on cancer cells and exhibits profound tumor-killing effects, the researchers report. “Compared to existing enzyme inhibitors, MS177 is more likely to perform much better for the treatment of patients with acute leukemias. To our knowledge, an agent for dual targeting of EZH2 and cMyc has not been developed. before.'” Greg Wang said. “MS177 thus represents a promising candidate for the treatment of other cancers based on the above tumorigenic pathways.”

Authors

In addition to Greg Wang, Jin and Jun Wang, the other authors of the article are Weida Gong, PhD, Xijuan Liu, PhD, Yi-Hsuan Tsai, PhD, David F. Allison, PhD, Ling Cai, PhD, UNC; Xufen Yu, PhD, Kwang-Su Park, PhD, Anqi Ma, PhD, Yudao Shen, PhD, and Jing Liu, PhD, Icahn School of Medicine at Mount Sinai, New York; Takashi Onikubo, PhD, and Robert G. Roeder, PhD, Rockefeller University, New York; Wen-Chieh Pi, PhD, and Wei-Yi Chen, PhD, National Yang Ming Chiao Tung University, Taipei, Taiwan.

This work was supported in part by grants from the National Institutes of Health, R01CA218600, R01CA268519, R01CA211336, R01CA215284, R01CA230854, and R01GM122749; Kimmel Scholarly Prize; Gabrielle’s Angel Foundation for Cancer Research; When everyone survives the Leukemia Research Foundation; and the University Cancer Research Fund. Wang is a researcher at the American Cancer Society, a researcher at the Leukemia and Lymphoma Society, and a researcher at the American Society of Hematology in basic sciences.

Yu, Ma, Shen, Lui and Jin are the inventors of the patent applications filed by the Icahn School of Medicine at Mount Sinai. Jin Lab has received research funding from Celgene Corporation, Levo Therapeutics, Cullgen, Inc. and Cullinan Oncology. Jin is a co-founder, Scientific Advisory Board member, and shareholder of Cullgen Inc., and a consultant for Cullgen Inc., EpiCypher Inc., and Accent Therapeutics Inc. The other authors declare no competing interests.