(Citarinostat) - 药物靶点：HDAC6_在研适应症：多发性骨髓瘤，阴燃多发性骨髓瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Citarinostat (USAN)

+ [2]

靶点

HDAC6

作用机制

HDAC6抑制剂(组蛋白去乙酰化酶-6抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [1]

在研适应症

多发性骨髓瘤阴燃多发性骨髓瘤

非在研适应症

晚期恶性实体瘤不可切除的黑色素瘤

原研机构

Acetylon Pharmaceuticals, Inc.

在研机构

OncoPep, Inc.

Celgene Corp.

Acetylon Pharmaceuticals, Inc.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C24H26ClN5O3

InChIKeyVLIUIBXPEDFJRF-UHFFFAOYSA-N

CAS号1316215-12-9

关联

5

项与 Citarinostat 相关的临床试验

NCT02886065 / Active, not recruiting临床1期

A Phase 1b Study of PVX-410, a Multi-Peptide Cancer Vaccine, and Citarinostat (CC-96241), a Histone Deacetylase Inhibitor (HDAC) With and Without Lenalidomide for Patients With Smoldering Multiple Myeloma

This research study is studying a targeted therapy as a possible treatment for Smoldering Multiple Myeloma.
The following intervention will be involved in this study:
Lenalidomide
Citarinostat (CC-96241)
PVX-410

开始日期2017-03-07

申办/合作机构

The General Hospital Corp.

[+2]

NCT02935790 / Completed临床1期

A Phase 1b Study of the Selective HDAC6 Inhibitor ACY-241 in Combination With Ipilimumab and Nivolumab in Patients With Unresectable Stage III or Stage IV Melanoma

Determine the safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of ACY-241 in combination with ipilimumab and nivolumab in patients with unresectable Stage III/Stage IV melanoma.

开始日期2016-09-30

申办/合作机构

Celgene Corp.

[+4]

NCT02635061 / Terminated临床1期

A Phase 1b Study of the Selective HDAC6 Inhibitor ACY-241 in Combination With Nivolumab in Patients With Unresectable Non-Small Cell Lung Cancer

Determine the safety, tolerability, dose limiting toxicities (DLTs), and maximum tolerated dose (MTD) of ACY 241 in combination with nivolumab.

开始日期2016-08-25

申办/合作机构

Celgene Corp.

100 项与 Citarinostat 相关的临床结果

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100 项与 Citarinostat 相关的转化医学

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100 项与 Citarinostat 相关的专利（医药）

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24

项与 Citarinostat 相关的文献（医药）

2024-01-01·The Korean Journal of Physiology & Pharmacology

ACY-241, a histone deacetylase 6 inhibitor, suppresses the epithelial–mesenchymal transition in lung cancer cells by downregulating hypoxia-inducible factor-1 alpha

Article

作者: Jeong, Chul-Ho ; Park, Seong-Jun ; Lee, Naeun

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1α activity is essential in normal tissues, its presence in the tumor microenvironment represents a significant risk factor as it can induce angiogenesis and confer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1α even under normoxia. In this study, we observed an inclination toward increased normoxic HIF-1α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF-1α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a significant reduction in HIF-1α expression upon HDAC6 inhibition. Moreover, the downregulation of HIF-1α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also demonstrated an inhibitory effect on cell invasion and migration by reducing HIF-1α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer.

2023-09-19·Biochemistry

Structure and Function of Kdac1, a Class II Deacetylase from the Multidrug-Resistant Pathogen Acinetobacter baumannii.

Article

作者: Watson, Paris R ; Christianson, David W

Proteomics studies indicate that 10% of proteins in the opportunistic pathogen Acinetobacter baumannii are acetylated, suggesting that lysine acetyltransferases and deacetylases function to maintain and regulate a robust bacterial acetylome. As the first step in exploring these fascinating prokaryotic enzymes, we now report the preparation and characterization of the lysine deacetylase Kdac1. We show that Kdac1 catalyzes the deacetylation of free acetyllysine and acetyllysine tetrapeptide assay substrates, and we also report the X-ray crystal structures of unliganded Kdac1 as well as its complex with the hydroxamate inhibitor Citarinostat. Kdac1 is a tetramer in solution and in the crystal; the crystal structure reveals that the L1 loop functions to stabilize quaternary structure, forming inter-subunit hydrogen bonds and salt bridges around a central arginine residue (R30). Surprisingly, the L1 loop partially blocks entry to the active site, but it is sufficiently flexible to allow for the binding of two Citarinostat molecules in the active site. The L12 loop is also important for maintaining quaternary structure; here, a conserved arginine (R278) accepts hydrogen bonds from the backbone carbonyl groups of residues in an adjacent monomer. Structural comparisons with two other prokaryotic lysine deacetylases reveal conserved residues in the L1 and L12 loops that similarly support tetramer assembly. These studies provide a structural foundation for understanding enzymes that regulate protein function in bacteria through reversible lysine acetylation, serving as a first step in the exploration of these enzymes as possible targets for the development of new antibiotics.

2023-07-27·Journal of medicinal chemistry1区 · 医学

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity.

1区 · 医学

Article

作者: Chai, Qipeng ; Liu, Chunxi ; Liu, Fengling ; Meng, Hongwei ; Zhang, Yingjie ; Yao, Tso-Pang ; Xue, Xia ; Zhao, Chunlong

In our previous research, a series of phenylsulfonylfuroxan-based hydroxamates were developed, among which compound 1 exhibited remarkable in vitro and in vivo antitumor potency due to its histone deacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities. Herein, the in-depth study of compound 1 revealed that this HDAC inhibitor-NO donor hybrid could enduringly increase the intracellular levels of acetyl histones and acetyl α-tubulin, which could be ascribed to its irreversible inhibition toward class I HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity. Furthermore, compound 4 could inhibit intracellular HDAC6 both selectively and irreversibly. To the best of our knowledge, this is the first research reporting the irreversible inhibition of HDAC6. It was also demonstrated that compared with ACY-241 (a reversible HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective inhibitor 4 exhibited not only superior anti-multiple myeloma activity but also improved therapeutic index.

100 项与 Citarinostat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10918	-	-	DB15449

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
不可切除的黑色素瘤	临床3期	美国	Celgene Corp.	2016-09-30
多发性骨髓瘤	临床2期	-	Acetylon Pharmaceuticals, Inc.	-
阴燃多发性骨髓瘤	临床1期	美国	OncoPep, Inc.	2017-03-07
晚期恶性实体瘤	临床1期	美国	Celgene Corp.	2015-12-22

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02400242 (ACE-MM-200, ASH2016) 人工标引	临床1期	多发性骨髓瘤	40	Pomalidomide+Dexamethasone+ACY-241	(願廠艱願憲鹽醖獵膚窪) = 1 grade 4 thrombocytopenia at 360 mg 鹽膚衊齋獵鹹遞餘選餘 (鏇膚遞繭獵壓範獵壓衊 ) 更多	积极	2016-12-02
NCT02635061 (Pubmed \| Front Oncol)	临床1期	晚期非小细胞肺癌	18	ACY-241	(膚廠醖製鏇築夢艱鹹艱) = 艱淵構壓積鑰選憲製淵獵醖淵壓餘衊鑰餘衊遞 (積積範製鹹餘醖糧積繭 )	-	2021-01-01
NCT02551185 (ASCO2018) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	20	paclitaxel+citarinostat	(艱糧範選製齋淵鬱願範) = citarinostat 360 mg/day 廠選糧廠襯獵繭淵積膚 (蓋願襯襯築獵遞衊鑰鹽 ) 更多	积极	2018-06-04