IC50: 5 nM (GCN2)[1]
GCN2-IN-7 (compound 39) is an orally active and selective general control nonderepressible 2 (GCN2) inhibitor (IC50=5 nM). GCN2-IN-7 shows anti-tumor activity in vivo[1].
GCN2-IN-7 (600 nM; 3 d) alleviates myeloid-derived suppressive cells (MDSC)-related T cell suppression and restores T cell proliferation[1].
Cell Proliferation Assay[1]
| Cell Line: | CD8+ T cells from WT and GCN2KO cells |
| Concentration: | 600 nM |
| Incubation Time: | 3 days |
| Result: | Relieved MDSC suppression of proliferation of the co-cultured CD8+ T cells with significant relief at 600 nM. |
GCN2-IN-7 (oral gavage; 15 mg/kg; BID; 17 d) shows robust target engagement in vivo at a reasonable dose[1].
GCN2-IN-7 (oral gavage; 50 mg/kg; BID; 17 d) inhibits tumor growth in vivo of the LL2 syngeneic mouse tumor model[1].
| Animal Model: | Balb/c mice injected with RENCA cells[1] |
| Dosage: | 15 mg/kg |
| Administration: | Oral gavage; 15 mg/kg; BID; 17 days |
| Result: | Showed robust target engagement of GCN2 in both tumor (average of 84%) and spleen (average of 80%) tissues. Showed an average of 65% reduction of downstream marker Activation Transcription Factor 4 (ATF4) in compound-treated mice compared to the vehicle treatment group. |
| Animal Model: | LL2 syngeneic mouse model[1] |
| Dosage: | 50 mg/kg |
| Administration: | Oral gavage; 50 mg/kg; BID; 17 days |
| Result: | Showed tumor growth inhibition (56%) after 26 days of dosing compared to the vehicle group. |
[1]. Jackson JJ, et al. Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy. J Med Chem. 2022 Sep 20.