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Description

A cell-permeable triazine compound that directly targets human E2 Ubiquitin-conjugating enzyme Rad6B/HHR6B catalytic site via noncovalent interactions and effectively inhibits Rad6B-Ub thioester bond formation as well as subsequent substrate ubiquitination without affecting UbcH5B/UBE2D2-catalyzed BCA2 ubiquitination. Shown to inhibit the proliferation of high Rad6B-expressing MDA-MB-231 (IC50 = 6 µ,M in 72 h), but not the low Rad6B-expressing, non-transformed MCF10A, via G2/M arrest and apoptosis induction. Two known cellular Rad6 substrates, beta-catenin and PCNA, are reported to be downregulated following 24 h inhibitor treatment in MDA-MB-231 cultures (0.5 to 5 µ,M)., A cell-permeable triazine compound that is reported to directly target human E2 Ubiquitin-conjugating enzyme Rad6B/HHR6B catalytic site via noncovalent interactions and effectively inhibit Rad6B-Ub thioester bond formation and subsequent Ub transfer to H2A (by 61%, 1 h 25 nM drug preincubation prior to 1 h H2A ubiquitination reactoin) without affecting UbcH5B/UBE2D2-catalyzed BCA2 ubiquitination. Shown to inhibit the proliferation of high Rad6B-expressing MDA-MB-231 (IC50 = 6 µ,M in 72 h by MTT assays, 96.3% inhibition of 24 h colony formation by 10 µ,M inhibitior) via G2/M arrest and apoptosis induction, while exhibiting little toxicity toward low Rad6B-expressing, non-transformed MCF10A (2% and 19% inhibition in 72 h by 10 and 50 µ,M inhibitor, respectively, by MTT assays). Two known cellular Rad6 substrates, beta-catenin and PCNA, are shown to be downregulated following 24 h inhibitor treatment in a dose-dependent manner in MDA-MB-231 cultures (0.5 to 5 µ,M).