KW-2478(KW-2478) - 药物靶点：HSP90B_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

HSP90B

作用机制

HSP90B抑制剂(热休克蛋白HSP 90β抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [2]

在研适应症-

非在研适应症

B细胞淋巴瘤慢性淋巴细胞白血病血液肿瘤+ [3]

原研机构

Kyowa Kirin Co., Ltd.

在研机构-

非在研机构

Kyowa Kirin Co., Ltd.Kyowa Hakko Kirin Uk Ltd.

最高研发阶段终止临床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C30H43ClN2O9

InChIKeyCKMGYWHSTADSIG-UHFFFAOYSA-N

CAS号819812-18-5

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关联

2

项与 KW-2478 相关的临床试验

NCT01063907 / Completed临床1/2期

An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination With Bortezomib in Subjects With Relapsed and/or Refractory Multiple Myeloma

The purpose of this study is to assess the safety and benefits of the investigational study drug, KW-2478, when given with bortezomib (Velcade®), a drug approved for the treatment of Multiple Myeloma (MM).
The primary objectives:
To establish the safety, tolerability, and recommended Phase II dose (RP2D) of KW-2478 in combination with bortezomib (Phase I);
To assess the overall response rate (ORR) when subjects with advanced MM are treated (Phase II).
The secondary objectives:
To characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of KW-2478 with bortezomib (Phase I only);
To evaluate for preliminary evidence of efficacy (Phase I);
To determine progression free survival (PFS) and duration of response of KW-2478 with bortezomib (Phase II).

开始日期2010-03-01

申办/合作机构

Kyowa Kirin Co., Ltd.

[+1]

NCT00457782 / Completed临床1期

A Phase I, Open-Label, Dose-escalation, Multicentre Study of KW-2478 Administered as a Single Agent Intravenously in a Consecutive Dosing Schedule in Patients With Relapsed/Refractory Multiple Myeloma, Chronic Lymphocytic Leukaemia or B-cell Non-Hodgkin's Lymphoma

The aim of this study is to determine the safety, tolerability and dose-limiting toxicities of KW-2478 and to determine the Maximum Tolerated Dose and recommended Phase II dose for patients with relapsed/refractory MM, CLL or B-cell NHL.

开始日期2007-04-01

申办/合作机构

Kyowa Kirin Co., Ltd.

[+1]

100 项与 KW-2478 相关的临床结果

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100 项与 KW-2478 相关的转化医学

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100 项与 KW-2478 相关的专利（医药）

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15

项与 KW-2478 相关的文献（医药）

2024-01-01·Journal of Biological Chemistry

HSP90AB1 is a host factor that promotes porcine deltacoronavirus replication

Article

作者: Chen, Rui ; Cao, Sanjie ; Yan, Qigui ; Zhao, Qin ; Zhao, Yujia ; Xiao, Dai ; Du, Senyan ; Wen, Xintian ; Song, Daili ; Zhang, Luwen ; Li, Cheng ; Yuan, Jianlin ; Hu, Jingfei ; Han, Xinfeng ; Wen, Yiping ; Wu, Rui ; Huang, Xiaobo

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and is of growing concern because of its broad host range, including humans. To date, the mechanism of PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen of PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes PDCoV infection. Knockdown or KO of HSP90AB1 in LLC-PK cells resulted in a significantly suppressed PDCoV infection. Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection. We found that HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV. We further evaluated the interaction between N and HSP90AB1 and found that the C-tail domain of the N protein is the HSP90AB1-interacting domain. Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research.

2022-12-01·Experimental Hematology & Oncology

The HSP90 inhibitor KW-2478 depletes the malignancy of BCR/ABL and overcomes the imatinib-resistance caused by BCR/ABL amplification

Article

作者: Wei, Wei ; Qin, Run ; Zeng, Dachuan ; Huang, Zhenglan ; Liu, Suotian ; Gao, Miao ; He, Wei ; Zheng, Renren

AbstractBackgroundWith the widespread clinical application of tyrosine kinase inhibitors (TKIs), an increasing number of chronic myeloid leukaemia (CML) patients have developed resistance or intolerance to TKIs. BCR/ABL is the oncoprotein of CML. HSP90 is an essential chaperone of BCR/ABL and plays an important role in protein folding and the function of BCR/ABL. Therefore, inhibiting the chaperone function of HSP90 may be an effective strategy for CML treatment and to overcome TKI resistance.MethodsThe effect of KW-2478 on CML cell viability, apoptosis and cell cycle progression was detected by CCK-8 assay or flow cytometry. The levels of BCR/ABL, HSP90 and other signalling proteins were detected by western blots. The mitochondrial membrane potential was detected by flow cytometry combined with JC-1 staining. The interaction between BCR/ABL and HSP90α was detected by coimmunoprecipitation. The effect of KW-2478 on BCR/ABL carcinogenesis in vivo was investigated in CML-like mouse models.ResultsKW-2478 inhibited growth and induced apoptosis of CML cells. KW-2478 inhibited the chaperone function of HSP90α and then weakened the BCR/ABL and MAPK signalling pathways. This treatment also caused an increase in p27 and p21 expression and a decrease in cyclin B1 expression, which led to G2/M phase arrest. The mitochondrial pathway was primarily responsible for KW-2478-induced apoptosis. KW-2478 had a synergistic effect with imatinib in growth inhibition. Notably, KW-2478 had a stronger effect on growth inhibition, apoptosis induction and cell cycle arrest of K562/G01 cells than K562 cells. KW-2478 could effectively prolong the mouse lifespan and alleviate disease symptoms in CML-like mouse models.ConclusionsThis finding demonstrated that KW-2478 had anticancer properties in imatinib-sensitive and imatinib-resistant CML cells and illustrated the possible mechanisms. This study provides an alternative choice for CML treatment, especially for TKI-resistant patients with BCR/ABL amplification and TKI-intolerant patients.

2022-02-01·Veterinary Microbiology2区 · 农林科学

HSP90 inhibitors 17-AAG and VER-82576 inhibit porcine deltacoronavirus replication in vitro

2区 · 农林科学

Article

作者: Wen, Yiping ; Yu, Enbo ; Zhao, Qin ; Cao, Sanjie ; Song, Daili ; Li, Shiqian ; Zhao, Yujia ; Du, Senyan ; Liao, Yijie ; Xiao, Dai ; Liu, Weizhe ; Zhang, Luwen ; Huang, Xiaobo ; Wen, Yimin ; Chen, Rui ; Wu, Rui ; Wen, Xintian

Porcine deltacoronavirus (PDCoV) is highly pathogenic to piglets, and no specific drugs or vaccines are available for the prevention and treatment of PDCoV infection, the need for antiviral therapies is pressing. HSP90 inhibitors have potent inhibitory effects against the replication of numerous viruses, hence we evaluated three HSP90 inhibitors, 17-AAG, VER-82576, and KW-2478, for their effects on PDCoV infection in vitro. We evaluated their effectivenesses at suppressing PDCoV by qRT-PCR, western blot, and TCID₅₀ assay, and found that 17-AAG and VER-82576 inhibited PDCoV at the early stage of replication, while KW-2478 showed no significant antiviral activity at any stage of infection. These results indicated that the PDCoV-inhibitory effects of 17-AAG and VER-82576 might be exerted by targeting host cell factor HSP90AB1 but not HSP90AA1. Further study showed that HSP90AB1 mRNA and protein levels were not significantly different in 17-AAG and VER-82576-treated cells versus control cells. 17-AAG and VER-82576 were also evaluated for their effects on the expressions of TNF-α, IL-6, and IL-12, which are PDCoV-induced proinflammatory cytokines. We found that both 17-AAG and VER-82576 inhibited the expressions of TNF-α, IL-6, and IL-12 to varying degrees, but in a dose dependent manner. From our data we can conclude that the HSP90 inhibitors 17-AAG and VER-82576 are promising candidates for the treatment of PDCoV infection.

100 项与 KW-2478 相关的药物交易

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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
浆细胞骨髓瘤难治	临床2期	美国	Kyowa Kirin Co., Ltd.	2010-03-01
浆细胞骨髓瘤难治	临床2期	菲律宾	Kyowa Kirin Co., Ltd.	2010-03-01
浆细胞骨髓瘤难治	临床2期	英国	Kyowa Kirin Co., Ltd.	2010-03-01
慢性淋巴细胞白血病	临床2期	英国	Kyowa Kirin Co., Ltd.	2007-04-01
慢性淋巴细胞白血病	临床2期	英国	Kyowa Hakko Kirin Uk Ltd.	2007-04-01
B细胞淋巴瘤	临床2期	-	Kyowa Kirin Co., Ltd.	-
血液肿瘤	临床2期	英国	Kyowa Kirin Co., Ltd.	-
多发性骨髓瘤	临床2期	美国	Kyowa Kirin Co., Ltd.	-
多发性骨髓瘤	临床2期	英国	Kyowa Kirin Co., Ltd.	-
多发性骨髓瘤	临床2期	菲律宾	Kyowa Kirin Co., Ltd.	-

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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


NCT01063907 (Pubmed \| Med J Aust) 人工标引	临床1/2期	多发性骨髓瘤	95	KW-2478+bortezomib	(構簾壓網簾鏇鬱膚積夢) = 鹽範膚選簾夢鹹顧鹽繭淵範網繭衊鏇簾衊醖顧 (壓醖願餘衊夢顧觸夢襯 ) 更多	积极	2017-10-24
NCT01063907 (CTgov)	临床1/2期	浆细胞骨髓瘤难治	95	KW-2478+Bortezomib (Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2)	繭構構蓋廠鹽鏇願鬱築(獵醖繭遞蓋廠選憲鹹鬱) = 簾艱網選餘範膚衊廠範遞餘餘餘窪繭鏇網餘淵 (積積遞選構醖衊憲夢簾, 繭窪夢鹹膚蓋鬱膚襯廠 ~ 蓋顧簾餘齋獵遞鬱廠襯) 更多	-	2014-11-05
NCT01063907 (CTgov)	临床1/2期	浆细胞骨髓瘤难治	95	KW-2478+Bortezomib (Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2)	繭構構蓋廠鹽鏇願鬱築(獵醖繭遞蓋廠選憲鹹鬱) = 構膚簾憲廠構繭餘蓋鏇遞餘餘餘窪繭鏇網餘淵 (積積遞選構醖衊憲夢簾, 鬱餘願鹽膚顧膚廠網製 ~ 觸憲網壓蓋窪製網鬱廠) 更多	-	2014-11-05