YCH2823 is an inhibitor of USP7 (IC50= 49.6 nM; Kd= 0.117 μM) and demonstrates significant efficacy in suppressing both wild-type TP53 tumors and mutated tumors. It is approximately 5 times more potent than FT671, induces apoptosis, and exhibits a synergistic effect with mTOR inhibitors.

USP7:49.6 nM

YCH2823 directly interacts with USP7, exhibiting high affinity and effectively inhibiting its enzymatic activity. It demonstrates potential low toxicity in IMR-90 cells (IC 50 > 20μM). YCH2823 (0-10 μM; 72 hours or 5 days) significantly suppresses cell proliferation in various tumor cell lines in a dose-dependent manner, showing high sensitivity towards both wild-type and mutant TP53. At concentrations of 0-1 μM over 1-48 hours, YCH2823 affects protein stability and cell cycle regulation. In LNCaP cells, it causes a rapid decrease in MDM2 protein levels and an increase in p53 and p21 levels. In MM.1S cells, while p53 protein levels remain mostly unchanged, p21 levels rise independently, suggesting a p53-independent pathway for p21 induction. In TP53 mutant Capan-1 cells, it leads to a significant reduction in Rad18 and DNMT1 proteins with a concurrent rise in p21 levels. YCH2823 (0-1 μM; 6-48 hours) induces the upregulation of BCL6 protein and mRNA, and promotes apoptosis by increasing the proportion of cells in the G1 phase in CHP212 and IMR-32 cells. DNMT1, p53, and p21 do not influence YCH2823-induced BCL6 upregulation. The combination of YCH2823 with Rapamycin or Ridaforolimus results in a synergistic effect, proving more effective than either drug alone.