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New Therapeutic Target Found for EZH2 Mutant Hematologic Malignancies
The inhibition of ubiquitin specific peptidase 47 (USP47) was identified as a novel therapeutic target for enhancer of zeste homolog 2 (EZH2) mutant hematologic malignancies.
Researchers used chemical genetic screening and combined preclinical models to discover small molecular compounds induced ubiquitin-mediated degradation of mutant EZH2, leading to cell death of both acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) in vitro and in vivo.
“We identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination,” elaborated Jing Wang, MD, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China, and co-researchers.
Further, degradation ubiquitination versus inhibition of catalytic activity is an innovative approach that may be beneficial for overcoming resistance to current EZH2 inhibitors, the researchers suggest.
“We propose targeting USP47 with a small molecular inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression,” concluded Dr Wang, et al.—Alexa Stoia
