Discovery of Novel Histone Deacetylase 6 (HDAC6) Inhibitors with Enhanced Antitumor Immunity of Anti-PD-L1 Immunotherapy in Melanoma

A series
of 2-phenylthiazole analogues were designed and synthesized
as potential histone deacetylase 6 (HDAC6) inhibitors based on compound 12c (an HDAC6/tubulin dual inhibitor discovered by us recently)
and CAY10603 (a known HDAC6 inhibitor). Among them, compound XP5 was the most potent HDAC6 inhibitor with an IC50 of 31 nM and excellent HDAC6 selectivity (SI = 338 for HDAC6 over
HDAC3). XP5 also displayed high antiproliferative activity
against various cancer cell lines including the HDACi-resistant YCC3/7
gastric cancer cells (IC50 = 0.16–2.31 μM),
better than CAY10603. Further, XP5 (50 mg/kg) exhibited
significant antitumor efficacy in a melanoma tumor model with a tumor
growth inhibition (TGI) of 63% without apparent toxicity. Moreover, XP5 efficiently enhanced the in vivo antitumor
immune response when combined with a small-molecule PD-L1 inhibitor,
as demonstrated by the increased tumor-infiltrating lymphocytes and
reduced PD-L1 expression levels. Taken together, the above results
suggest that XP5 is a promising HDAC6 inhibitor deserving
further investigation.