HDAC6型
化学
黑色素瘤
癌症研究
IC50型
组蛋白脱乙酰基酶
组蛋白脱乙酰酶抑制剂
免疫疗法
体内
药理学
免疫系统
细胞毒性
癌症免疫疗法
体外
组蛋白
生物化学
免疫学
生物
生物技术
基因
作者
Xiaopeng Peng,Ling Li,Jingxuan Chen,Yichang Ren,Jin Liu,Ziwen Yu,Hao Cao
标识
DOI:10.1021/acs.jmedchem.1c01863
摘要
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.
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