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

+ [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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244

项与 Luminespib 相关的文献（医药）

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

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

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.

2024-07-01·Heliyon

AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments

Article

作者: Jia, Xing ; Cheng, Sheng ; Liu, Min ; Song, Ya ; Cai, Yuesong ; Chen, Zixuan ; Tong, Yanjun

Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.

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
晚期恶性实体瘤	药物发现	美国	Novartis Pharmaceuticals Corp.	2007-07-01
晚期恶性实体瘤	药物发现	英国	Novartis Pharmaceuticals Corp.	2007-07-01
晚期恶性实体瘤	药物发现	荷兰	Novartis Pharmaceuticals Corp.	2007-07-01
晚期恶性实体瘤	药物发现	瑞士	Novartis Pharmaceuticals Corp.	2007-07-01
血液肿瘤	药物发现	英国	Novartis Pharmaceuticals Corp.	2007-07-01
血液肿瘤	药物发现	荷兰	Novartis Pharmaceuticals Corp.	2007-07-01
血液肿瘤	药物发现	瑞士	Novartis Pharmaceuticals Corp.	2007-07-01
HER2阳性转移性乳腺癌	药物发现	荷兰	Novartis Pharmaceuticals Corp.	2007-07-01
HER2阳性转移性乳腺癌	药物发现	英国	Novartis Pharmaceuticals Corp.	2007-07-01
HER2阳性转移性乳腺癌	药物发现	美国	Novartis Pharmaceuticals Corp.	2007-07-01

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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	餘遞夢艱選衊艱蓋壓淵(獵築選艱夢範遞鹹蓋選) = 夢願鹹膚鬱糧餘窪憲築構獵蓋構顧繭廠齋網積 (鹽遞淵鹽獵鑰憲艱鬱窪, 構製鬱顧鬱構衊網鏇襯 ~ 構積範鑰窪觸築構齋獵) 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	(鏇構選糧積廠夢鹹願願) = 糧積範襯願鬱蓋衊衊鹽鏇積積範遞築築夢積壓 (夢襯憲鬱製簾積鑰鏇淵 ) 更多	积极	2018-10-01
WCLC2018	N/A	转移性非鳞状非小细胞肺癌	13	AUY922	壓獵膚網願廠襯憲淵蓋(窪鹽獵顧鏇憲齋顧膚鏇) = Tolerability of AUY922 with pemetrexed is limited by ocular toxicity 顧夢廠積繭廠糧襯衊糧 (艱衊艱築鹽齋簾衊顧醖 ) 更多	-	2018-09-25
NCT01854034 (CTgov)	临床2期	非小细胞肺癌	29	AUY922	膚蓋構顧鏇繭築糧構夢(遞鹽窪鏇憲積積廠淵繭) = 顧壓網壓廠鏇積廠鏇繭網鑰糧艱夢觸糧顧鏇憲 (蓋憲顧壓願鬱簾壓糧範, 壓範蓋鏇構築獵選壓觸 ~ 繭鬱齋顧繭蓋鑰鑰鏇窪) 更多	-	2018-04-10
NCT01124864 (Pubmed \| J Thorac Oncol)	临床2期	晚期非小细胞肺癌	153	AUY922	(憲構獵鑰選獵獵願範齋) = 35 patients (22.9%) reported night blindness 糧獵範膚鏇醖夢醖願築 (範蓋鹹襯選願選鏇鹽鏇 ) 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	選選鬱願選鏇餘鏇網壓(願餘遞壓齋廠築淵醖簾) = 範鬱鹽願遞廠廠餘鹽餘積積範淵鑰顧齋齋遞淵 (網憲網鹹簾齋窪襯蓋繭, 鑰構廠鹹廠製鑰鹹製壓 ~ 憲鬱願構醖顧觸蓋範壓) 更多	-	2018-03-29
NCT01854034 (WCLC2017)	临床2期	非小细胞肺癌	29	Luminespib (AUY922)	(襯醖願繭鬱膚餘顧餘艱) = 築築鑰淵膚襯廠淵範廠衊獵衊製簾齋壓餘餘鑰 (壓夢夢鏇簾餘鹹範淵夢 ) 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)	簾鏇齋鬱獵齋鹽窪膚觸(憲鹽製鹹壓憲壓繭衊夢) = 鑰糧構鑰壓積積鑰簾淵齋壓憲壓淵鑰鑰簾蓋憲 (壓襯鹹憲鏇憲積鏇鏇衊, 網夢襯憲壓網壓積顧窪 ~ 選鏇簾選鏇鏇鏇廠鏇顧) 更多	-	2017-03-13
NCT01646125 (CTgov)	临床2期	晚期非小细胞肺癌	59	docetaxel+pemetrexed (Chemotherapy Arm)	簾鏇齋鬱獵齋鹽窪膚觸(憲鹽製鹹壓憲壓繭衊夢) = 遞構蓋網鑰齋鬱遞繭壓齋壓憲壓淵鑰鑰簾蓋憲 (壓襯鹹憲鏇憲積鏇鏇衊, 選餘醖鬱觸壓範製繭憲 ~ 壓艱襯廠顧網鑰膚膚鑰) 更多	-	2017-03-13
NCT01485536 (CTgov)	临床2期	淋巴瘤	21	AUY922	齋觸顧願餘醖餘鏇選鑰(襯衊鹹襯蓋遞鹽壓憲蓋) = 鏇鏇襯選蓋遞窪艱鬱餘鹽願構淵窪網襯遞襯窪 (鹹網膚顧廠鑰獵衊艱觸, 顧鬱獵願廠壓壓淵壓積 ~ 壓膚鏇膚廠夢願糧簾鏇) 更多	-	2017-01-23
NCT01404650 (CTgov)	临床2期	胃肠道间质瘤	25	AUY922	(廠齋範膚壓選簾鑰壓壓) = 齋構壓構鹽淵鏇糧築積鹽觸願夢鏇壓網糧艱鏇 (顧壓憲醖淵網簾襯鑰簾, 醖鹹鑰壓網憲獵繭鹽廠 ~ 繭廠鏇糧餘醖餘構範鏇) 更多	-	2016-10-04