PD-L1/HDAC6-IN-1 TFA is an orally active dual inhibitor of PD-L1 and HDAC6, with IC50 values of 26.8 nM and 78 nM, respectively. PD-L1/HDAC6-IN-1 TFA binds to human and murine PD-L1 proteins with high affinity, while it reduces STAT3 phosphorylation and downregulates PD-L1 expression by inhibiting HDAC6, thus blocking the PD-1/PD-L1 interaction. PD-L1/HDAC6-IN-1 TFA exhibits potent anti-tumor activity in a mouse melanoma model. PD-L1/HDAC6-IN-1 is suitable for research on tumor immune regulation related to melanoma [1].
In Vivo, PD-L1/HDAC6-IN-1 (HP29) (20 mg/kg; i.p., once daily for 14 days) TFA significantly suppresses tumor growth with a tumor growth inhibition (TGI) rate of 65.5% in the B16-F10 melanoma model, induces no obvious body weight loss or systemic toxicity, markedly elevates the percentages of tumor-infiltrating CD3+CD4+ and CD3+CD8+ lymphocytes, and significantly reduces PD-L1 protein expression while increasing acetylated α-tubulin levels in tumor tissues[1].
In Vitro, PD-L1/HDAC6-IN-1 (HP29) (0.1-2.0 μM; 12 h) TFA upregulates the level of acetylated α-tubulin in B16-F10 cells and Jurkat cells[1]. PD-L1/HDAC6-IN-1 (0.1-2.0 μM; 24 h) TFA downregulates the expression of p-STAT3 and PD-L1 in B16-F10 cells[1]. PD-L1/HDAC6-IN-1 TFA shows negligible cytotoxicity against B16-F10, HepG2, MCF-7 and Jurkat cells[1]. PD-L1/HDAC6-IN-1 (0.01-10 μM; 48 h) TFA shows negligible cytotoxicity against HepG2 cells and Jurkat T cells, while dose-dependently increasing the mortality of HepG2 cells co-cultured with Jurkat T cells with an IC50 of 3.4 μM[1]. PD-L1/HDAC6-IN-1 TFA dose-dependently activates luciferase activity in PD-1/PD-L1 NFAT reporter assay (EC50 = 3.15 μM)[1]. PD-L1/HDAC6-IN-1 TFA binds to human PD-L1 and murine PD-L1 with KD values of 179 nM and 73 nM in the ITC assay, and 464 nM and 55.3 nM in the SPR assay, respectively[1].
References:
[1]. Hu Z, et al. Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy. J Med Chem. 2025;68(5):5426-5454.
In Vivo, PD-L1/HDAC6-IN-1 (HP29) (20 mg/kg; i.p., once daily for 14 days) TFA significantly suppresses tumor growth with a tumor growth inhibition (TGI) rate of 65.5% in the B16-F10 melanoma model, induces no obvious body weight loss or systemic toxicity, markedly elevates the percentages of tumor-infiltrating CD3+CD4+ and CD3+CD8+ lymphocytes, and significantly reduces PD-L1 protein expression while increasing acetylated α-tubulin levels in tumor tissues[1].
In Vitro, PD-L1/HDAC6-IN-1 (HP29) (0.1-2.0 μM; 12 h) TFA upregulates the level of acetylated α-tubulin in B16-F10 cells and Jurkat cells[1]. PD-L1/HDAC6-IN-1 (0.1-2.0 μM; 24 h) TFA downregulates the expression of p-STAT3 and PD-L1 in B16-F10 cells[1]. PD-L1/HDAC6-IN-1 TFA shows negligible cytotoxicity against B16-F10, HepG2, MCF-7 and Jurkat cells[1]. PD-L1/HDAC6-IN-1 (0.01-10 μM; 48 h) TFA shows negligible cytotoxicity against HepG2 cells and Jurkat T cells, while dose-dependently increasing the mortality of HepG2 cells co-cultured with Jurkat T cells with an IC50 of 3.4 μM[1]. PD-L1/HDAC6-IN-1 TFA dose-dependently activates luciferase activity in PD-1/PD-L1 NFAT reporter assay (EC50 = 3.15 μM)[1]. PD-L1/HDAC6-IN-1 TFA binds to human PD-L1 and murine PD-L1 with KD values of 179 nM and 73 nM in the ITC assay, and 464 nM and 55.3 nM in the SPR assay, respectively[1].
References:
[1]. Hu Z, et al. Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy. J Med Chem. 2025;68(5):5426-5454.