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.