A452(A452) - 药物靶点：HDACs_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

HDACs

作用机制

HDAC抑制剂(组蛋白去乙酰化酶家族抑制剂)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

Yonsei University

在研机构

Yonsei University

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C20H22N2O3

InChIKeyZIQAJFVTKUTVEP-UHFFFAOYSA-N

CAS号798543-42-7

关联

100 项与 A452 相关的临床结果

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100 项与 A452 相关的转化医学

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100 项与 A452 相关的专利（医药）

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1

项与 A452 相关的文献（医药）

2017-04-01·Cancer Letters1区 · 医学

HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis

1区 · 医学

Article

作者: Lee, Dong Hoon ; Choi, Junjeong ; Han, Gyoonhee ; Ryu, Hyun-Wook ; Shin, Dong-Hee ; Kwon, So Hee ; Lee, Kang Young

HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation. A452 blocked HDAC6 nuclear localization, resulting in increased levels of acetylated p53 at Lys381/382. HDAC6 bound to the C-terminal region of p53 via its deacetylase domain. A452 disrupted the HDAC6-Hsp90 chaperone machinery via Hsp90 acetylation and degradation. Furthermore, it chemosensitized cancer cells to the Hsp90 inhibitor 17-AAG. Overall, silencing of HDAC6 showed similar effects. These findings suggest that the anticancer action of HDAC6 inhibitors requires p53 and Hsp90 and targeting of HDAC6 may represent a new therapeutic strategy for cancers regardless of p53's mutation status.

100 项与 A452 相关的药物交易

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