Luminespib(Luminespib) - 药物靶点：HSP90_在研适应症：头颈部肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Luminespib (USAN/INN)、Luminespib Mesylate、AUY-922

+ [3]

靶点

HSP90

作用机制

HSP90 抑制剂(Heat shock 90kDa proteins inhibitors)

治疗领域

肿瘤

在研适应症

头颈部肿瘤

非在研适应症

肺腺癌晚期胃癌晚期 HER2 阳性乳腺癌+ [26]

原研机构

Ligand UK Ltd.

在研机构

The Institute of Cancer Research: Royal Cancer Hospital

非在研机构

Novartis Pharmaceuticals Corp.

北京诺华制药有限公司

Novartis AG

+ [1]

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)无进展

特殊审评特殊审批 (中国)

登录后查看时间轴

结构/序列

分子式C26H31N3O5

InChIKeyNDAZATDQFDPQBD-UHFFFAOYSA-N

CAS号747412-49-3

关联

28

项与 Luminespib 相关的临床试验

ACTRN12614000789662

/ Not yet recruiting临床2期IIT

A Randomised controlled Phase II trial of the pharmacodynamic effects of the heat shock protein 90 (Hsp90) inhibitor AUY922 in high-risk, localised prostate cancer

开始日期2016-08-01

申办/合作机构

The University of Sydney

CTR20140725

/ Completed临床2期

AUY922、BYL719、INC280、LDK378和MEK162多臂单药治疗晚期非小细胞肺癌（NSCLC）患者的II期、开放性、临床研究

本研究的目的是评估AUY922、BYL719、INC280、LDK378和MEK162多臂单药治疗具有特定分子异常的晚期NSCLC患者的抗肿瘤活性。

开始日期2015-01-20

申办/合作机构

Novartis Pharmaceuticals Corp.

[+2]

NCT01784640

/ Completed临床1期IIT

A Phase IB Dose-Escalation Study of Pemetrexed and AUY922 in Previously-Treated Patients With Metastatic Non-Squamous, Non-Small Cell Lung Cancer

This phase I trial studies the side effects and the best dose of Hsp90 inhibitor AUY922 when given together with pemetrexed disodium in treating patients with previously treated stage IV non-small cell lung cancer. Hsp90 inhibitor AUY922 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pemetrexed disodium, work in different ways to stop the growth of tumor cell, either by killing the cells or stopping them from dividing. Giving Hsp90 inhibitor AUY922 together with pemetrexed disodium may kill more tumor cells

开始日期2014-01-31

申办/合作机构

Jonsson Comprehensive Cancer Center

[+2]

100 项与 Luminespib 相关的临床结果

登录后查看更多信息

100 项与 Luminespib 相关的转化医学

登录后查看更多信息

100 项与 Luminespib 相关的专利（医药）

登录后查看更多信息

247

项与 Luminespib 相关的文献（医药）

2025-02-01·LIFE SCIENCES

NVP-AUY922 relieves radiation-induced intestinal injury via regulating EPHX1

Article

作者: Wang, Zhaoyu ; Fan, Saijun ; Lu, Lu ; Ding, Xudong ; Kong, Wenzhe

As a common side effect of radiotherapy, radiation-induced intestinal injury (RIII) greatly affects the prognosis of patients and the efficacy of radiotherapy. Current therapeutic strategies for RIII are still very limited. Thus, the identification of effective radioprotective agents is of great importance. NVP-AUY922 is an HSP90 inhibitor with favorable anti-inflammatory and antioxidant activities. It has been proven to mitigate radiation-induced lung injury. However, its effects on the alleviation of RIII remain unclear. In this study, our data indicated that NVP-AUY922 remarkably increased the survival rate after radiation exposure. NVP-AUY922 treatment could enhance the viability of intestinal stem cells (ISCs) and promote the recovery of the small intestine. In addition, it also inhibited intestinal inflammation and reshaped the gut microbiota structure. We found that the radioprotective effect of NVP-AUY922 is partially dependent on EPHX1. In addition, NVP-AUY922 could attenuate dextran sulfate sodium (DSS)-induced colitis and promote intestinal barrier recovery. Thus, our results suggest that NVP-AUY922 contributes to the amelioration of intestinal injury after radiation exposure, which offers a new approach for the prevention of RIII.

2025-02-01·CANCER LETTERS

HSP90 inhibitor AUY922 suppresses tumor growth and modulates immune response through YAP1-TEAD pathway inhibition in gastric cancer

Article

作者: Wang, Linghua ; Scott, Ailing W ; Jin, Jiankang ; Yao, Xiaodan ; Waters, Rebecca E ; Shao, Shan ; Fan, Yibo ; Yin, Feng ; Yoshimura, Katsuhiro ; Wang, Lingzhi ; Dhar, Shilpa S ; Brown, Calena-Abel ; Yamashita, Kohei ; Pizzi, Melissa Pool ; Gan, Qiong ; Ajani, Jaffer A ; Wang, Ruiping ; Wu, Jingjing ; Zou, Gengyi ; Song, Shumei

Heat shock protein 90 (HSP90), a vital chaperone involved in the folding and stabilization of various cellular proteins, regulates key functions in many tumor cells. In the context of gastric adenocarcinoma (GAC), where HSP90's role remains largely unexplored, we aimed to investigate the significance of HSP90 inhibitor, AUY922, in regulating the YAP1/TEAD pathway and its association with the tumor immune microenvironment (TME). Our results showed that AUY922 effectively inhibited GAC aggressiveness in both the invitro and invivo models, induced apoptosis, and cell-cycle arrest. Various functional assays elucidated that AUY922 potently inhibited the expression and interaction among YAP1/TEAD and HSP90, resulting in down-regulation of target functional genes. AUY922 additionally altered the tumor microenvironment (TME) into an inflamed state with increased cytokine production in T cells, including interferon gamma, granzyme B, and perforin, and inhibited M2 polarization of tumor-associated macrophages, rendering it a favorable partner for immune checkpoint inhibition. Our findings highlighted the suggestion of targeting HSP90 in GAC therapy via down-regulating YAP1/TEAD signaling. Additionally, our results suggest that AUY922's ability to reshape the GAC TME favoring the host sets the stage for a clinical trial that combines HSP90 and checkpoint inhibition, where HSP90 could serve as a biomarker for patient selection.

2024-11-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids

Article

作者: Zhao, Jian-Xun ; Hsu, Kai-Cheng ; Chang, Hung-Hsuan ; Lai, Mei-Jung ; Liu, Zheng-Yang ; Cho, Er-Chieh ; Chen, I-Chung ; Chen, Mei-Chuan ; Tsai, Kelvin K. ; Cheng, Li-Hsin ; Lin, Tony Eight ; Tang, Di-Wei ; Liou, Jing-Ping ; Chou, Po-Yu ; Tsai, Kelvin K

The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI₅₀ values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.

1

项与 Luminespib 相关的新闻（医药）

2024-07-04

·医药魔方Pro

让PROTAC更有效，这篇论文值得一看 | Nature子刊

靶向蛋白降解策略通过使用小分子降解剂（如PROTAC），来诱导致病蛋白快速降解，为癌症等疾病的治疗提供了新思路。体内信号通路如何影响蛋白降解的效果？7月2日，Nature Communications杂志发表了一篇论文，作者确定了调节BRD4、BRD2/3、CDK9等靶点PROTAC靶向降解的细胞信号通路。他们通过验证，确定了一些化合物——如PDD00017273（一种PARG抑制剂，下文简称PDD)、GSK2606414（一种PERK抑制剂，下文简称GSK)、luminespib（一种HSP90抑制剂)——均是降解增强剂。这些结果表明，各种细胞内在的信号通路在多个步骤影响蛋白降解的效果。首先，为了确定调节靶向降解的信号通路，研究人员筛选了存在或不存在MZ1（一种基于CRL2VHL的BRD4 PROTAC）的情况下，BRD4降解的变化。结果表明，引入各种细胞内在信号通路后，可能会自发抑制BRD4靶向降解，BRD4可以被特异性抑制剂释放。图1. 调控BRD4靶向降解途径的筛选接下来，研究人员分析了HeLa细胞中内源性BRD4的降解。结果发现，PARG抑制PDD可促进BRD4和BRD2/3的靶向降解，但不促进MEK1/2或ERα的靶向降解。图2. PARG抑制促进BRD4的靶向蛋白降解在发现PDD对PARG的抑制能显著促进PROTAC诱导的BRD4降解后，研究人员探究了PDD的作用是在哪个步骤起作用的。结果发现，PARG抑制促进BRD4-MZ1-CRL2VHL系列三元复合物形成和K29/K48支链泛素化。此外，研究人员还发现，抑制HSP90可促进BRD4在泛素化步骤后降解。图3. PARG抑制促进BRD4-MZ1-CRL2VHL系列三元复合物的形成和K29/K48支链泛素化接下来，研究人员又探索了相关机制，他们发现，PERK或HSP90抑制剂都是主要的蛋白抑制途径，通过影响泛素-蛋白酶体途径的不同步骤来调节BRD4的化学诱导降解。此外，研究人员还探究了PROTAC增强剂是否可以促进高效降解剂诱导的靶向降解。SIM1是最近开发的一种三价PROTAC，可更有效地诱导BRD-PROTAC-CRL2VHL三元复合物的形成，以及随后BRD4和BRD2/3的降解。结果发现，使用SIM1+PDD或SIM1+GSK的共同治疗，比单独使用SIM1的治疗更有效地诱导细胞死亡。最后，研究人员想知道，这些信号抑制剂是否也促进其他激酶（如CDK9）的活性，结果发现，PARG抑制不仅可以有效降解BRD家族蛋白，还可以降解CDK9。论文作者表示：“我们预计随后的筛选会鉴定出许多细胞通路，这些通路的鉴定将有助于阐明靶向蛋白质降解的机制。” 注：文章配图均来自论文参考资料： Yuki Mori et al. Intrinsic signaling pathways modulate targeted protein degradation. Nature Communications（2024） https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-49519-z Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

蛋白降解靶向嵌合体临床结果

100 项与 Luminespib 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D10646	Luminespib	-	-

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
头颈部肿瘤	临床2期	英国	The Institute of Cancer Research: Royal Cancer Hospital	2023-01-30
肺腺癌	临床2期	中国	Novartis Pharma AG	2015-01-20
肺腺癌	临床2期	中国	Novartis Pharmaceuticals Corp.	2015-01-20
肺腺癌	临床2期	中国	北京诺华制药有限公司	2015-01-20
肺腺癌	临床2期	新加坡	Novartis Pharma AG	2015-01-20
肺腺癌	临床2期	新加坡	北京诺华制药有限公司	2015-01-20
肺腺癌	临床2期	新加坡	Novartis Pharmaceuticals Corp.	2015-01-20
原发性血小板增多症后骨髓纤维化	临床2期	美国	Novartis AG	2012-08-01
真性红细胞增多症后骨髓纤维化	临床2期	美国	Novartis AG	2012-08-01
原发性骨髓纤维化	临床2期	美国	Novartis AG	2012-08-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01259089 (CTgov)	临床1/2期	非小细胞肺癌IIIB期	38	needle biopsy+erlotinib hydrochloride+Hsp90 inhibitor AUY922	願餘繭襯蓋襯範醖蓋廠(窪餘鬱遞衊醖獵願獵蓋) = 蓋積遞廠艱廠廠憲窪壓鏇鏇餘淵鏇齋壓積窪醖 (繭繭窪艱壓選鑰構窪淵, 窪壓窪願衊築窪鹽簾製 ~ 膚鹽衊醖衊膚齋鏇遞鑰) 更多	-	2018-11-21
NCT01854034 (Pubmed \| Ann Oncol)	临床2期	EGFR 20号外显子插入突变非小细胞肺癌	29	Luminespib	網簾襯鑰糧鹹糧淵觸衊(構膚觸廠鏇夢壓選襯衊) = 獵膚廠衊繭窪網築繭夢壓繭構遞餘構觸簾壓艱 (鹹襯鑰觸願壓繭選壓願 ) 更多	积极	2018-10-01
WCLC2018	N/A	转移性非鳞状非小细胞肺癌	13	AUY922	範膚鹽獵構繭築齋願餘(顧衊網獵淵網積製醖製) = Tolerability of AUY922 with pemetrexed is limited by ocular toxicity 餘餘膚糧艱齋壓簾艱夢 (積簾糧願衊壓蓋衊艱壓 ) 更多	-	2018-09-25
NCT01854034 (CTgov)	临床2期	非小细胞肺癌	29	AUY922	夢鏇蓋淵觸憲構願膚餘(遞製鑰簾簾齋選廠艱襯) = 鑰夢積鹹積遞鏇鑰選壓醖艱夢選獵獵顧窪壓淵 (鏇餘淵築窪廠膚製製餘, 鏇餘膚艱衊鑰廠餘膚積 ~ 膚鏇襯製齋鹹簾願壓鑰) 更多	-	2018-04-10
NCT01124864 (Pubmed \| J Thorac Oncol)	临床2期	晚期非小细胞肺癌	153	AUY922	襯鏇餘築夢襯選遞鹽齋(鹽鑰製齋顧廠蓋遞淵襯) = 35 patients (22.9%) reported night blindness 艱蓋願糧膚餘夢鏇蓋齋 (憲範齋鹽夢夢範艱鬱襯 ) 更多	-	2018-04-01
NCT01752400 (CTgov)	临床2期	ALK阳性肺癌 \| ALK阳性非小细胞肺癌	6	AUY922	夢醖壓壓鹽願齋顧鏇網(願獵廠製蓋襯網遞壓蓋) = 夢壓艱選鹹憲膚淵艱築網憲顧簾遞築膚築艱範 (鬱糧膚遞積膚網蓋鏇鏇, 艱鹽蓋觸壓鹽鑰構憲鏇 ~ 網壓衊積網鹹齋獵顧醖) 更多	-	2018-03-29
NCT01854034 (WCLC2017)	临床2期	非小细胞肺癌	29	Luminespib (AUY922)	夢築廠夢獵網繭顧壓廠(淵觸願願鬱廠壓襯夢窪) = 製憲構膚構窪糧遞鬱夢選遞範鹽糧壓憲範鑰膚 (選製鏇積鹹廠糧夢簾顧 ) 更多	积极	2017-10-18
NCT01646125 (CTgov)	临床2期	晚期非小细胞肺癌	59	AUY922 (AUY922 Arm)	壓夢範鏇遞壓鬱繭夢觸(壓鑰願淵觸鬱鹽鏇鏇蓋) = 淵遞膚襯選衊顧糧鏇簾顧淵網積獵鏇襯膚鑰鹹 (糧鹽網鬱廠選製鹹鹹窪, 簾構網遞鹽壓觸繭壓網 ~ 繭範簾衊鬱構醖鬱顧願) 更多	-	2017-03-13
NCT01646125 (CTgov)	临床2期	晚期非小细胞肺癌	59	docetaxel+pemetrexed (Chemotherapy Arm)	壓夢範鏇遞壓鬱繭夢觸(壓鑰願淵觸鬱鹽鏇鏇蓋) = 鑰顧願窪繭積鹽鑰艱獵顧淵網積獵鏇襯膚鑰鹹 (糧鹽網鬱廠選製鹹鹹窪, 築鹹繭鑰淵鑰襯醖繭糧 ~ 壓簾繭選繭糧鏇壓築夢) 更多	-	2017-03-13
NCT01485536 (CTgov)	临床2期	复发性淋巴瘤 \| 淋巴瘤	21	AUY922	範憲憲鬱網餘選膚壓襯(網膚夢齋繭鏇鬱鬱鹽襯) = 範鬱構淵顧鏇構遞憲憲艱鹹繭餘顧鹹憲構衊鏇 (醖範簾淵遞醖觸獵醖鏇, 鹽鏇糧願憲壓憲醖憲鏇 ~ 齋衊醖鏇艱築製繭鏇艱) 更多	-	2017-01-23
NCT01404650 (CTgov)	临床2期	胃肠道间质瘤	25	AUY922	構鹹築襯製夢簾積築餘(願膚廠衊蓋顧簾築襯鹽) = 構壓膚膚鹹鏇衊簾選衊選糧醖構繭積衊積簾築 (鬱蓋蓋膚簾繭糧蓋醖襯, 蓋網鏇醖遞築鹽鹹醖膚 ~ 遞淵製夢觸觸範糧蓋糧) 更多	-	2016-10-04