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 <b>HP29</b> 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 <b>HP29</b> could bind with high affinity to PD-L1 and HDAC6 protein. Furthermore, <b>HP29</b> possessed favorable <i>in vivo</i> pharmacokinetic properties, such as decent oral bioavailability (<i>F</i> = 15.3%). Moreover, <b>HP29</b> exhibited significant <i>in vivo</i> 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 <b>HP29</b>-treated tumor tissues were significantly higher than the combination group or PD-L1 inhibitor monotherapy group, suggesting potential synergistic antitumor immune effects. Collectively, <b>HP29</b> represents a novel PD-L1/HDAC6 dual inhibitor deserving further investigation as a potential cancer immunomodulating agent.