Discovery of novel biphenyl compounds bearing hydroxamic acid moiety as the first PD-L1/class I HDACs dual inhibitors

Herein, we firstly reported a series of biphenyl compounds bearing hydroxamic acid moiety as PD-L1/class I HDACs dual inhibitors. Among them, compound <b>14</b> displayed the strongest inhibitory activity <i>in vitro</i> against HDAC2 and HDAC3 with IC₅₀ values of 27.98 nM and 14.47 nM, and had an IC₅₀ value of 88.10 nM for PD-1/PD-L1 interaction. Importantly, <b>14</b> could upregulate the expression of PD-L1 and CXCL10 in a PD-L1 low-expression cancer cell line (MCF-7), highlighting the potential to enhance efficacy by recruiting T-cell infiltration into TME and improving the response of PD-1/PD-L1 inhibitor associated with PD-L1 low-expression. Besides, we identified another compound, <b>22</b>, which possessed the strongest inhibitory activity against PD-1/PD-L1 interaction with an IC₅₀ value of 12.47 nM, and effectively inhibited the proliferation of three cancer cell lines. Our results suggest that compounds <b>14</b> and <b>22</b> can be served as lead compounds of PD-L1/class I HDACs dual inhibitors for further optimisation.