ArticlePharmaceutical research2025
Synthesis and Biological Evaluation of Novel Triazine Analogs as Rad6 Inhibitors.
Article in Pharmaceutical research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
Rad6 is an E2 ubiquitin-conjugating enzyme that plays critical roles in genome maintenance and proteostasis. Rad6 is frequently overexpressed in many cancers and promotes cancer development, progression, and chemotherapy resistance. PURPOSE: Given its role in cancer development and progression, Rad6 is an underexplored therapeutic target. Previous research identified compound SMI#9 as a small molecule inhibitor of Rad6. Despite its potency, SMI#9 has limited efficacy in vivo due to its limiting water solubility and the presence of a labile ester group.
methodsTo address these limitations, we prepared a series of SMI#9 analogs in which the ester group was replaced with a secondary amine, and their effects on Rad6B-mediated ubiquitination of histone H2A were evaluated. In vivo interaction with Rad6 was assessed using cellular thermal shift assays. SMI#9 analog effects on cell survival and migration of triple negative and endocrine-resistant breast cancer, and melanoma cells were measured using MTT and Boyden chamber assays. Autophagy, mitochondrial function, and β-catenin localization were measured using CytoID, Mitotracker, and immunostaining, respectively. Cellular uptakes of analogs were determined by mass spectroscopy.
resultsAnalogs #4 and #6 inhibited H2A ubiquitination, induced autophagy and mitochondrial dysfunction, downregulated intracellular β-catenin, and inhibited proliferation. #6 targets Rad6 in vivo. #4 and #6 are chemically related, and #4 undergoes in vivo conversion to #6.
conclusions#6 retains all the properties of SMI#9 but with lesser potency. However, its improved water solubility and metabolic stability allows for in vivo studies that were previously precluded due to the poor physicochemical properties of SMI#9.
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