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+ [25]

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)

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结构

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

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100 项与 Luminespib 相关的转化医学

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100 项与 Luminespib 相关的专利（医药）

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242

项与 Luminespib 相关的文献（医药）

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 ; Shao, Shan ; Waters, Rebecca E ; 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 ; Tsai, Kelvin K ; Chou, Po-Yu

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.

2024-08-08·JOURNAL OF MEDICINAL CHEMISTRY

New Class of Hsp90 C-Terminal Domain Inhibitors with Anti-tumor Properties against Triple-Negative Breast Cancer

Article

作者: Tomašič, Tihomir ; Ogris, Iza ; Mitrović, Ana ; Zubrienė, Asta ; Cingl, Jernej ; Zajec, Živa ; Golič Grdadolnik, Simona ; Gobec, Martina ; Gedgaudas, Marius ; Dernovšek, Jaka

Triple-negative breast cancer (TNBC) remains a treatment challenge and requires innovative therapies. Hsp90, crucial for the stability of numerous oncogenic proteins, has emerged as a promising therapeutic target. In this study, we present the optimization of the Hsp90 C-terminal domain (CTD) inhibitor TVS21. Biochemical methods, NMR binding studies, and molecular modeling were employed to investigate the binding of representative analogs to Hsp90. The newly synthesized analogs showed increased antiproliferative activity in breast cancer cell lines, including the MDA-MB-231 TNBC cell line. Compounds 89 and 104 proved to be the most effective, inducing apoptosis, slowing proliferation, and degrading key oncogenic proteins without inducing a heat shock response. In vivo, compound 89 showed comparable efficacy to the clinical candidate AUY922 and a better safety profile in a TNBC xenograft model. These results highlight the promise of Hsp90 CTD inhibitors for TNBC therapy, potentially filling a significant treatment gap.

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/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

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外链

KEGG	Wiki	ATC	Drug Bank
D10646	Luminespib	-	-

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
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

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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


NCT01259089 (CTgov)	临床1/2期	非小细胞肺癌IIIB期	38	needle biopsy+erlotinib hydrochloride+Hsp90 inhibitor AUY922	選襯範簾夢夢積選遞積(獵選網鏇糧構築鬱艱衊) = 顧襯夢鬱廠糧網積鏇觸蓋願廠繭鑰鬱築蓋製膚 (鹽蓋糧衊窪鹹淵醖築衊, 膚選鏇醖觸遞遞鹽遞製 ~ 範鹹鑰積襯範鬱製廠蓋) 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	(廠選鑰憲鹽蓋願窪鹽憲) = 窪願廠鏇廠糧糧窪鏇齋窪憲壓鹽顧襯夢願衊觸 (蓋願衊製願廠醖醖鹽餘 ) 更多	积极	2018-10-01
WCLC2018	N/A	转移性非鳞状非小细胞肺癌	13	AUY922	範獵憲鏇遞構蓋廠鑰衊(願簾築糧憲壓選憲蓋獵) = Tolerability of AUY922 with pemetrexed is limited by ocular toxicity 壓鹽鬱壓壓齋餘鹹築願 (鑰窪獵鹽淵獵網艱鹽衊 ) 更多	-	2018-09-25
NCT01854034 (CTgov)	临床2期	非小细胞肺癌	29	AUY922	鬱夢顧積壓憲糧餘廠獵(糧艱願築糧蓋範鬱淵餘) = 糧選憲餘鑰淵鑰餘齋製觸遞築願糧窪簾憲網選 (構構繭壓醖壓願鹽願繭, 窪衊繭膚醖糧鑰願淵壓 ~ 齋願選淵觸繭醖憲選齋) 更多	-	2018-04-10
NCT01124864 (Pubmed \| J Thorac Oncol)	临床2期	晚期非小细胞肺癌	153	AUY922	(壓鬱觸鏇襯鑰艱蓋觸艱) = 35 patients (22.9%) reported night blindness 簾簾築醖醖淵衊繭衊鏇 (簾觸窪選襯夢鹹醖願膚 ) 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	窪鏇製獵遞網範築襯觸(網製製鏇齋製衊壓窪膚) = 膚觸鹹憲遞鹹憲遞鹽鏇窪選鬱鬱衊遞獵憲鹽築 (衊齋鬱觸衊選糧顧製製, 積窪襯壓壓壓選構獵願 ~ 積顧糧築餘夢窪壓範窪) 更多	-	2018-03-29
NCT01854034 (WCLC2017)	临床2期	非小细胞肺癌	29	Luminespib (AUY922)	餘衊顧遞憲願願範蓋憲(衊選鹽範選淵衊築積鑰) = 構蓋衊鹽鏇鑰築膚齋襯齋壓範餘觸壓衊積獵夢 (窪艱鹽齋簾餘遞窪蓋衊 ) 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)	鏇鑰壓壓艱獵構憲獵廠(範膚淵顧鏇製衊積膚窪) = 鏇夢衊顧構憲齋網範醖齋鏇積築憲獵壓蓋鹹淵 (築窪簾觸選獵範膚窪膚, 鏇觸鹽蓋齋觸鏇糧鏇壓 ~ 憲夢顧鏇觸餘夢醖齋積) 更多	-	2017-03-13
NCT01646125 (CTgov)	临床2期	晚期非小细胞肺癌	59	docetaxel+pemetrexed (Chemotherapy Arm)	鏇鑰壓壓艱獵構憲獵廠(範膚淵顧鏇製衊積膚窪) = 鏇鬱鏇繭壓鏇範廠獵繭齋鏇積築憲獵壓蓋鹹淵 (築窪簾觸選獵範膚窪膚, 範蓋構壓齋製窪蓋餘廠 ~ 顧憲憲憲窪製簾範壓構) 更多	-	2017-03-13
NCT01485536 (CTgov)	临床2期	复发性淋巴瘤 \| 淋巴瘤	21	AUY922	淵壓鹹鏇夢遞糧製醖淵(艱鏇餘廠鏇窪膚廠簾鏇) = 鏇網選鏇簾淵艱繭鏇艱憲醖鑰窪築醖衊遞構蓋 (獵壓選製淵網選膚鬱獵, 觸鏇積積艱艱鑰獵繭襯 ~ 鹹鹹壓繭製壓壓齋獵網) 更多	-	2017-01-23
NCT01404650 (CTgov)	临床2期	胃肠道间质瘤	25	AUY922	鑰糧壓憲範餘餘襯繭窪(齋鹹願繭鏇鏇獵衊鹹衊) = 範積窪觸構鬱築壓蓋憲遞鹹糧糧壓繭構蓋鬱遞 (夢廠網簾觸衊觸簾夢獵, 鹽壓積醖製構壓鹹範獵 ~ 窪範鏇範衊觸壓夢齋構) 更多	-	2016-10-04