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.

本研究以我们近期发现的HDAC6/微管蛋白双重抑制剂化合物12c，以及已知HDAC6抑制剂CAY10603为骨架，设计并合成了一系列2-苯基噻唑类似物，作为潜在的组蛋白去乙酰化酶6（HDAC6）抑制剂。其中，化合物XP5为活性最优的HDAC6抑制剂，其半数抑制浓度（IC50）为31 nM，且对HDAC6具备优异选择性，相对于HDAC3的选择性指数（SI）达338。XP5对多种癌细胞系均展现出优异的抗增殖活性，包括对HDAC抑制剂耐药的YCC3/7胃癌细胞（IC50=0.16~2.31 μM），其活性优于CAY10603。进一步研究显示，XP5（50 mg/kg）在黑色素瘤移植瘤模型中展现出显著的抗肿瘤功效，肿瘤生长抑制率（TGI）达63%，且未观察到明显毒性反应。此外，当与小分子PD-L1（programmed death-ligand 1）抑制剂联用时，XP5可有效增强体内抗肿瘤免疫应答，具体表现为肿瘤浸润淋巴细胞数量增多以及PD-L1表达水平下调。综上，上述研究结果表明，XP5是一款极具开发前景的HDAC6抑制剂，值得开展进一步的深入研究。