| Literature DB >> 33979648 |
Yannick D Benoit1, Ryan R Mitchell2, Wenliang Wang3, Luca Orlando4, Allison L Boyd4, Borko Tanasijevic2, Lili Aslostovar2, Zoya Shapovalova2, Meaghan Doyle4, Christopher J Bergin5, Kinga Vojnits4, Fanny L Casado2, Justin Di Lu2, Deanna P Porras4, Juan Luis García-Rodriguez4, Jennifer Russell2, Aïcha Zouggar5, Angelique N Masibag5, Cody Caba6, Kalinka Koteva6, Lakshmana K Kinthada6, Jagdish Suresh Patel7, Sara N Andres6, Jakob Magolan8, Tony J Collins2, Gerard D Wright9, Mickie Bhatia10.
Abstract
Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.Entities:
Keywords: SUMOylation; drug; leukemia; natural products; screening; selectivity; stem cells
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Year: 2021 PMID： 33979648 PMCID： PMC8542640 DOI： 10.1016/j.chembiol.2021.04.014
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 9.039