Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy

A series of novel PD-L1/HDAC6 dual inhibitors were designed and synthesized, and compound HP29 was identified as the most potent candidate, which demonstrated excellent and selective HDAC6 inhibitory activity (IC50 = 78 nM, SI > 1282), and high anti-PD-1/PD-L1 activity (IC50 = 26.8 nM). Further studies showed that HP29 could bind with high affinity to PD-L1 and HDAC6 protein. Furthermore, HP29 possessed favorable in vivo pharmacokinetic properties, such as decent oral bioavailability (F = 15.3%). Moreover, HP29 exhibited significant in vivo antitumor efficacy in a melanoma tumor model with a greater tumor growth inhibition (TGI) (65.5%) than that of NP19 (43.2%), ACY-1215 (45.6%), and the combination group (53.9%). Mechanistically, the percentages of tumor-infiltrating lymphocytes (TILs) in the HP29-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, HP29 represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential cancer immunomodulating agent.