FIGURE 1.

YH29407 with improved pharmacodynamics and pharmacokinetics reduced tumor growth via activation of the T cell-mediated immune response in a syngeneic MC38 tumor-bearing model. Syngeneic MC38 colon tumor was grafted onto C57BL/6 mice and treatment was started when the tumor volume reached 50 mm³. Epacadostat and BMS-986205 were treated as comparators, and tumor and serum were obtained after 5 days of treatment (A). IDO1 inhibition with YH29407 (100 mg/kg, B.I.D.) significantly suppresses the growth of MC38 tumor in C57BL/6 mice compared to the comparator (B). Tumor volume and number of individual mice (C). Tumor growth inhibition was enhanced by the IDO1 inhibitor, with 60% of mice treated with YH29407 (100 mg/kg, B.I.D.) showing more than 50% TGI (D). Improved pharmacodynamics in the MC38 mouse tumor model (E) and human SKOV-3 tumor model (F). (G) Analysis of T cell subset by flow cytometry. Effector T cells, IFN-γ+ Tc, and Th cells were increased in the YH29407 (100 mg/kg, B.I.D.) group compared to other groups. However, CD4⁺ Treg was decreased in the YH29407 (100 mg/kg, B.I.D.) group. Heatmap (H) and volcano plot (I) of cytokine array using serum of YH29407 (100 mg/kg, B.I.D.) and vehicle treated mice showed that EMT signature proteins were decreased and T cell activation cytokines were increased after treatment of YH29407. Statistical significance between groups of (B) was calculated using two-way ANOVA followed by Tukey’s multiple comparisons tests (**p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001), likewise (G) was calculated using student’s t-test (*p < 0.05). ANOVA, analysis of variance; Trp, tryptophan; Kyn, kynurenine; IFN-γ+, interferon γ; EMT, epithelial-mesenchymal transition; ANOVA, analysis of variance.