XL-888(XL-888) - 药物靶点：HSP90B_在研适应症：不可切除的黑色素瘤_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

肿瘤皮肤和肌肉骨骼疾病

在研适应症

不可切除的黑色素瘤

非在研适应症

异戊酸血症大肠腺癌复发性结直肠癌+ [3]

原研机构

Exelixis, Inc.

在研机构

Genentech, Inc.

Exelixis, Inc.

非在研机构

Merck Sharp & Dohme Corp.

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C29H37N5O3

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CAS号1149705-71-4

关联

4

项与 XL-888 相关的临床试验

NCT03095781 / Completed临床1期IIT

Phase Ib Trial of Pembrolizumab and XL888 in Patients With Advanced Gastrointestinal Malignancies

This phase Ib trial studies the side effects and best dose of Hsp90 inhibitor XL888 when given together with pembrolizumab in treating patients with advanced gastrointestinal cancer that has spread to other places in the body. XL888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving XL888 with pembrolizumab may work better in treating patients with gastrointestinal cancer.

开始日期2017-07-07

申办/合作机构

Emory University

[+4]

NCT02721459 / Active, not recruiting临床1期IIT

Phase I Study of Escalating Doses of XL888 With Vemurafenib Plus Cobimetinib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

The main purpose of this study is to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of XL888 when administered orally with vemurafenib plus cobimetinib in participants with BRAF V600 mutated melanoma and to evaluate the safety and tolerability of this combination.

开始日期2016-09-07

申办/合作机构

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+2]

NCT01657591 / Completed临床1期IIT

Phase I Study of Escalating Doses of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

This is a multi-cohort, dose-escalation study of XL888 with a fixed dose of vemurafenib. New dose escalation or de-escalation cohorts will be assigned by the Principal Investigator (PI) with discussion with appropriate co-investigators once safety and tolerability is known for a given cohort in accordance to dose escalation rules. Participants will be defined to be enrolled within a cohort upon receipt of first dose of XL888/vemurafenib.

开始日期2012-07-27

申办/合作机构

H. Lee Moffitt Cancer Center & Research Institute, Inc.

[+1]

100 项与 XL-888 相关的临床结果

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100 项与 XL-888 相关的转化医学

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100 项与 XL-888 相关的专利（医药）

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18

项与 XL-888 相关的文献（医药）

2024-09-13·Current medicinal chemistry

Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity.

Article

作者: Medrasi, Hanadi Y ; Abbas, Eman M H ; Farghaly, Thoraya A ; Sabour, Rehab ; Alsaiari, Norah A ; Kassem, Asmaa F

BACKGROUND AND OBJECTIVEBreast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).METHODSNovel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90.RESULTSAll tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.CONCLUSIONWe have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.

2024-05-01·Journal of Clinical Investigation

An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis

Article

作者: Zhou, Minqi ; Arkin, Michelle R ; Peng, Tien ; Krasilnikov, Maria ; Ravishankar, Supriya ; Lee, Jin Young ; Wolters, Paul J ; Wilson, Chris ; Ringler, Christian ; Sheppard, Dean ; Pohan, Grace ; Ang, Kenny Kean-Hooi ; Tsukui, Tatsuya ; Reyes, Nabora S

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues, termed senolytics. However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision-cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor, XL888, as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-hi human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mice and humans, respectively, and provides a senolytic screening platform for other age-related diseases.

2024-04-01·Cell Chemical Biology

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome

Article

作者: Sylvester, Kayla ; Hughes, Philip F ; Fitzgerald, Michael C ; Derbyshire, Emily R ; Leahy, James W ; Ryan, Daniel H ; Eduful, Benjamin ; Quan, Baiyi ; Chirgwin, Michael E ; Mansfield, Christopher R ; Kafsack, Björn F C ; Haystead, Timothy A J ; Neveu, Gaëlle

The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target.

100 项与 XL-888 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12981

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
异戊酸血症	申请上市	美国	Merck Sharp & Dohme Corp.	2017-07-07
异戊酸血症	申请上市	美国	Exelixis, Inc.	2017-07-07
复发性结直肠癌	申请上市	美国	Exelixis, Inc.	2017-07-07
复发性结直肠癌	申请上市	美国	Merck Sharp & Dohme Corp.	2017-07-07
大肠腺癌	临床1期	美国	Merck Sharp & Dohme Corp.	2017-07-07
遗传性非息肉病性结直肠癌1型	临床1期	美国	Merck Sharp & Dohme Corp.	2017-07-07
遗传性非息肉病性结直肠癌1型	临床1期	美国	Exelixis, Inc.	2017-07-07
不能切除性胰腺癌	临床1期	美国	Exelixis, Inc.	2017-07-07
不能切除性胰腺癌	临床1期	美国	Merck Sharp & Dohme Corp.	2017-07-07
不可切除的黑色素瘤	临床1期	美国	Exelixis, Inc.	2012-07-27

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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


NCT03095781 (ESMO_GI2024) 人工标引	临床1期	晚期结直肠腺癌三线 \| \|	16	Pembrolizumab+XL888	(糧餘鹹餘襯鏇襯艱築鹽) = 顧選網簾鹽醖網簾鑰積糧鑰壓鏇積構構鏇齋鬱 (簾構鹹願淵膚淵餘願憲 ) 更多	不佳	2024-06-27
NCT03095781 (ESMO_GI2024) 人工标引	临床1期	结直肠癌 RAS \| BRAF \| HER2 amplification	16	Pembrolizumab+XL888	(鹹艱獵衊網齋簾艱願鹹) = 獵簾製遞選鬱鑰餘淵鑰蓋窪蓋壓觸淵網築獵糧 (鏇築簾製醖網憲積夢積, 3.0 ~ 9.9) 更多	不佳	2024-06-20
NCT03095781 (330, SITC2020)	临床1/2期	转移性消化系统癌 Hsp90 \| PD-1	-	XL888 and pembrolizumab	餘繭願鑰壓齋鬱憲鬱鹹(膚鏇選艱醖觸願獵餘壓) = 齋衊積夢夢鏇構觸廠鏇獵遞鹽壓糧蓋構衊廠範 (壓廠餘鏇鑰網餘構遞鑰 )	积极	2020-12-10
NCT03095781 (330, SITC2020)	临床1/2期	转移性消化系统癌 Hsp90 \| PD-1	-	Pembrolizumab	餘繭願鑰壓齋鬱憲鬱鹹(膚鏇選艱醖觸願獵餘壓) = 餘淵壓鹹壓顧壓鏇窪鹹獵遞鹽壓糧蓋構衊廠範 (壓廠餘鏇鑰網餘構遞鑰 )	积极	2020-12-10
NCT03095781 (ASCO_GI2020) 人工标引	临床1期	肿瘤	-	XL888+pembrolizumab	(餘鑰鏇遞遞範製艱構餘) = XL888 90 mg twice weekly combined with P 200 mg, every 3 weeks 選醖願遞製齋構鹹糧齋 (廠壓餘鏇夢醖鹽網蓋夢 ) 更多	积极	2020-01-23
NCT02721459 (ASCO2019)	临床1期	黑色素瘤	25	Vemurafenib 960 mg PO BID + Cobimetinib 60 mg QD for 21 of 28 days + XL888 30 mg PO twice weekly	鬱製夢餘鑰餘鹽顧膚觸(鹽鹽繭構鹽鑰鑰夢艱鬱) = 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose 淵夢選鬱窪憲蓋齋醖鑰 (窪網醖構顧網獵餘醖願 ) 更多	不佳	2019-05-26
NCT02721459 (ASCO2019)	临床1期	黑色素瘤	25	Vemurafenib 720 mg PO BID + Cobimetinib 40 mg QD for 21 of 28 days + XL888 60 mg PO twice weekly		不佳	2019-05-26
NCT01657591 (ASCO2016) 人工标引	临床1期	转移性黑色素瘤 BRAF V600 Mutation	19	vemurafenib+XL888	(餘蓋餘獵膚鹹醖製鹽醖) = 蓋淵蓋繭繭築醖鹹淵糧膚艱夢構窪膚簾顧願蓋 (膚鹹鏇鬱網網鹽鑰廠襯, 3.7 ~ 16.2) 更多	积极	2016-06-04