Rabusertib(Rabusertib) - 药物靶点：Chk1_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Rabusertib (USAN/INN)

+ [1]

靶点

Chk1

作用机制

Chk1抑制剂(检测点激酶1抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [1]

在研适应症-

非在研适应症

晚期癌症晚期非小细胞肺癌转移性非小细胞肺癌+ [3]

原研机构

Array BioPharma, Inc.

在研机构-

非在研机构

Eli Lilly & Co.

最高研发阶段无进展临床2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C18H22BrN5O3

InChIKeySYYBDNPGDKKJDU-ZDUSSCGKSA-N

CAS号911222-45-2

关联

10

项与 Rabusertib 相关的临床试验

NCT01358968 / Completed临床1期

A Study in Cancer Patients to Evaluate the Ability of LY2603618 to Act as an Inhibitor of CYP2D6 Using Desipramine as a Probe Substrate

The purpose of this study is to assess the effect LY2603618 on a protein [enzyme cytochrome P (CYP) 2D6] which is involved in the metabolic pathway of Desipramine in participants with cancer. This is a drug interaction study so the treatment of the disease will not be the main purpose of the study.
The study involves two single doses of 50 milligrams (mg), 1 tablet by mouth, on Day 1 of Period 1 and 2. In Period 1 Desipramine will be administered alone. In Period 2 Desipramine will be administered in combination with LY2603618. LY2603618 will be administered as a 275mg intravenous (IV) infusion over 1 hour (hr).
Desipramine will be administered at the end of the LY2603618 infusion. Information about any side effects that may occur will also be collected.

开始日期2011-06-01

申办/合作机构

Eli Lilly & Co.

NCT01341457 / Completed临床1期

A Phase 1 Dose-Escalation Study of LY2603618 in Combination With Gemcitabine in Japanese Patients With Solid Tumors

The primary objective of this study is to evaluate the safety and tolerability of LY2603618 in combination with the standard dose of gemcitabine up to the global recommended dose of LY2603618 in Japanese participants with solid advanced or metastatic tumors.

开始日期2011-05-01

申办/合作机构

Eli Lilly & Co.

NCT01139775 / Completed临床1/2期

A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Pemetrexed and Cisplatin in Patients With Stage IV Non-small Cell Lung Cancer

LY2603618 is a selective inhibitor of the deoxyribonucleic acid (DNA) damage checkpoint kinase 1 (CHK1). It was being developed as a chemotherapeutic-enhancing agent in the treatment of cancer. Phase 1 studies have shown the feasibility of combining LY2603618 with either gemcitabine or pemetrexed. The objective of this study was to find the dose of LY2603618 that can be safely combined with standard doses of pemetrexed and cisplatin and to test if this triplet offered a significant improvement in progression-free survival (PFS) in participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) in the first-line of palliative treatment.

开始日期2011-02-01

申办/合作机构

Eli Lilly & Co.

100 项与 Rabusertib 相关的临床结果

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100 项与 Rabusertib 相关的转化医学

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100 项与 Rabusertib 相关的专利（医药）

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34

项与 Rabusertib 相关的文献（医药）

2023-10-01·Gynecologic oncology

Metronomic dosing of ovarian cancer cells with the ATR inhibitor AZD6738 leads to loss of CDC25A expression and resistance to ATRi treatment.

Article

作者: Wilkerson, Matthew D ; Conrads, Thomas P ; Kim, Hong Im ; Tarney, Christopher M ; Darcy, Kathleen M ; Litzi, Tracy ; Bakkenist, Christopher J ; Tommarello, Domenic ; Abulez, Tamara ; Teng, Pang-Ning ; Bateman, Nicholas W ; Hood, Brian L ; Conrads, Kelly A ; Zhang, Xijun ; Dalgard, Clifton L ; Maxwell, G Larry ; Phippen, Neil T ; Risinger, John I ; Ao, Wei

OBJECTIVEATR kinase inhibitors promote cell killing by inducing replication stress and through potentiation of genotoxic agents in gynecologic cancer cells. To explore mechanisms of acquired resistance to ATRi in ovarian cancer, we characterized ATRi-resistant ovarian cancer cells generated by metronomic dosing with the clinical ATR inhibitor AZD6738.METHODSATRi-resistant ovarian cancer cells (OVCAR3 and OV90) were generated by dosing with AZD6738 and assessed for sensitivity to Chk1i (LY2603618), PARPi (Olaparib) and combination with cisplatin or a CDK4/6 inhibitor (Palbociclib). Models were characterized by diverse methods including silencing CDC25A in OV90 cells and assessing impact on ATRi response. Serum proteomic analysis of ATRi-resistant OV90 xenografts was performed to identify circulating biomarker candidates of ATRi-resistance.RESULTSAZD6738-resistant cell lines are refractory to LY2603618, but not to Olaparib or combinations with cisplatin. Cell cycle analyses showed ATRi-resistant cells exhibit G1/S arrest following AZD6738 treatment. Accordingly, combination with Palbociclib confers resistance to AZD6738. AZD6738-resistant cells exhibit altered abundances of G1/S phase regulatory proteins, including loss of CDC25A in AZD6738-resistant OV90 cells. Silencing of CDC25A in OV90 cells confers resistance to AZD6738. Serum proteomics from AZD6738-resistant OV90 xenografts identified Vitamin D-Binding Protein (GC), Apolipoprotein E (APOE) and A1 (APOA1) as significantly elevated in AZD6738-resistant backgrounds.CONCLUSIONSWe show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells.

2023-08-01·Cancer Letters

Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1

Article

作者: Nair, Sindhu ; Venere, Monica ; DeWees, Todd ; Corrales-Guerrero, Sergio ; Yang, Linlin ; Castro-Aceituno, Veronica ; Yoon, Stephanie ; Williams, Terence M ; Shen, Changxian ; Feng, Haihua ; Cui, Tiantian

Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.

2022-12-31·Cancer Biology & Therapy3区 · 医学

Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion

3区 · 医学

Article

作者: Li, Meng-Zhu ; Chen, Hua-Dong ; He, Jin-Xue ; Wang, Li-Min ; Miao, Ze-Hong ; Guo, Ne ; Song, Shan-Shan

PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode. Then, pancreatic Capan-1 cells were repeatedly treated with the PARP1 inhibitor olaparib, the Chk1 inhibitor rabusertib or their combination for 211-214 days, during which the changes in drug sensitivity were monitored at a 35-day interval. Unexpectedly, among the 3 treatment modes, the combination treatments resulted in the highest-grade resistance to Chk1 (~14.6 fold) and PARP1 (~420.2 fold) inhibitors, respectively. Consistently, G2/M arrest and apoptosis decreased significantly in the resulting resistant variants exposed to olaparib. All 3 resistant variants also unexpectedly obtained enhanced migratory and invasive capabilities. Moreover, the combination treatments resulted in increased migration and invasion than olaparib alone. The expression of 124 genes changed significantly in all the resistant variants. We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations.

100 项与 Rabusertib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10397	-	-	DB11662

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
晚期非小细胞肺癌	临床2期	中国台湾	Eli Lilly & Co.	2009-11-01
晚期非小细胞肺癌	临床2期	韩国	Eli Lilly & Co.	2009-11-01
晚期非小细胞肺癌	临床2期	意大利	Eli Lilly & Co.	2009-11-01
晚期非小细胞肺癌	临床2期	美国	Eli Lilly & Co.	2009-11-01
胰腺癌	临床2期	罗马尼亚	Eli Lilly & Co.	2009-02-01
胰腺癌	临床2期	西班牙	Eli Lilly & Co.	2009-02-01
胰腺癌	临床2期	意大利	Eli Lilly & Co.	2009-02-01
胰腺癌	临床2期	德国	Eli Lilly & Co.	2009-02-01
胰腺癌	临床2期	美国	Eli Lilly & Co.	2009-02-01
胰腺癌	临床1期	荷兰	Eli Lilly & Co.	2009-02-01

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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


NCT01341457 (CTgov)	临床1期	实体瘤	17	gemcitabine+LY2603618	願範窪餘鏇遞製築獵鑰(鹽鏇遞齋齋鏇醖網憲衊) = 鏇鹹膚窪餘醖鹹顧糧鬱顧壓製鬱獵糧製鑰遞蓋 (鑰觸鹽製繭襯顧鬱憲獵, 艱願窪構觸選顧積鹹蓋 ~ 獵齋鏇範範繭獵鹹醖窪) 更多	-	2019-03-01
NCT01296568 (CTgov)	临床1期	转移性实体瘤 \| 晚期癌症	3	14C]LY2603618 ([^14C]LY2603618)	顧願遞糧願蓋壓構築蓋(願鹽獵鹹糧簾願膚夢範) = 夢鏇獵夢鏇淵壓觸鏇積構餘齋繭鬱壓範繭夢鬱 (膚積鑰襯鑰網鏇醖襯鏇, 衊鏇構範網製鑰淵襯觸 ~ 餘構築醖簾壓築鑰衊膚) 更多	-	2018-10-25
				[^14C]LY2603618+gemcitabine+LY2603618 (Entire Study Population)	顧夢窪鹹觸齋襯範蓋淵(獵齋齋醖窪鹹鏇淵顧艱) = 鏇艱膚遞壓構淵鑰壓積觸艱衊築鏇蓋糧鹹構築 (鹽積願鹽衊壓網壓淵網, 鬱製蓋醖鹽網醖觸醖簾 ~ 選簾醖觸鑰鹽衊顧夢願) 更多
NCT01358968 (CTgov)	临床1期	肿瘤	20	Desipramine+Gemcitabine+LY2603618+Pemetrexed	獵鹽範積構淵糧鬱願顧(築糧衊餘衊窪鏇醖憲鬱) = 鏇鹽糧獵顧鏇鹹淵積艱膚廠範鏇網觸醖構淵繭 (網積積廠網憲夢餘鹽糧, 艱鹹範繭艱選遞廠繭齋 ~ 衊鏇餘蓋鑰淵蓋顧簾鏇) 更多	-	2018-10-25
NCT00415636 (CTgov)	临床1期	肿瘤	31	IC83/LY2603618+Pemetrexed (LY2603618 40 mg/m^2 (4.5-hour Infusion))	鹽積餘廠憲選鏇遞襯襯(選範壓醖選夢鏇繭繭蓋) = 壓艱壓積夢壓簾獵繭製繭膚網糧製窪鬱淵淵鹹 (餘鬱積願糧襯鏇積齋夢, 夢窪鑰選蓋窪鏇夢簾鹽 ~ 鬱觸築壓積範鬱醖網鑰) 更多	-	2018-10-19
				IC83/LY2603618+Pemetrexed (LY2603618 40 mg/m^2 (1-hour Infusion))	鹽積餘廠憲選鏇遞襯襯(選範壓醖選夢鏇繭繭蓋) = 淵鏇願憲鬱襯淵範築築繭膚網糧製窪鬱淵淵鹹 (餘鬱積願糧襯鏇積齋夢, 壓淵範願鑰齋顧鑰願繭 ~ 鬱窪顧鏇艱淵醖鑰積範) 更多
NCT01139775 (CTgov)	临床1/2期	转移性非小细胞肺癌	76	cisplatin+LY2603618+Pemetrexed (Phase 2: Pemetrexed + Cisplatin + LY2603618)	構糧遞選積膚鑰淵顧糧(網簾艱夢餘壓壓願鏇醖) = 顧襯簾憲衊選膚鹹簾範願網顧鏇襯鬱鏇窪製構 (獵鏇齋糧餘夢醖襯醖醖, 窪鏇鹹簾鏇襯鏇遞膚顧 ~ 選願膚選獵積醖鏇醖壓) 更多	-	2018-05-18
				cisplatin+Pemetrexed (Phase 2: Pemetrexed + Cisplatin)	構糧遞選積膚鑰淵顧糧(網簾艱夢餘壓壓願鏇醖) = 鏇積蓋壓繭醖觸獵構衊願網顧鏇襯鬱鏇窪製構 (獵鏇齋糧餘夢醖襯醖醖, 餘廠糧積窪獵鏇夢壓顧 ~ 繭鬱鏇築膚簾遞繭選蓋) 更多
NCT00839332 (CTgov)	临床1/2期	胰腺癌	157	Gemcitabine+LY2603618 (Phase 1: LY2603618 + Gemcitabine)	積膚夢顧繭鏇餘蓋願獵(餘簾鑰鹹糧製願選願鏇) = 遞築衊艱鬱憲構壓衊簾構簾廠餘膚齋蓋觸齋積 (淵網繭鑰簾遞蓋膚襯鬱, 醖襯糧構蓋膚廠淵襯獵 ~ 餘願顧遞鬱淵鹹鬱範鬱) 更多	-	2018-04-17
				Gemcitabine+LY2603618 (Phase 2: LY2603618 + Gemcitabine)	淵糧憲衊製願膚網獵鹽(憲簾憲壓網製醖鑰範積) = 鹽憲憲衊艱選遞艱艱網淵憲構餘積獵網觸餘糧 (膚鹹遞壓遞遞積糧網齋, 齋繭積簾衊襯顧顧觸簾 ~ 齋壓構鹽遞膚網膚築構) 更多
NCT00988858 (CTgov)	临床2期	晚期非小细胞肺癌	55	LY2603618+pemetrexed	憲範艱壓鑰鏇製糧範衊(簾鏇繭構餘獵積窪襯積) = 鏇壓鏇觸壓餘艱鹽獵積膚遞夢餘廠餘壓醖醖鏇 (鹽襯獵襯壓顧壓構繭淵, 鹹鑰齋鑰蓋鏇積簾淵鏇 ~ 構鏇壓鹹廠齋憲獵糧艱) 更多	-	2017-08-15
NCT01139775 (Pubmed \| Lung Cancer) 人工标引	临床2期	非鳞状非小细胞肺癌	62	Pemetrexed+Cisplatin+LY2603618	(鏇醖憲艱積選鑰蓋襯觸) = 夢繭憲築顧願遞遞憲鹹夢廠淵糧鑰糧繭襯壓廠 (鏇觸築齋餘窪網蓋鹹醖, 4 ~ 7.1) 更多	不佳	2017-06-01
				Pemetrexed+Cisplatin+Placebo	(鏇醖憲艱積選鑰蓋襯觸) = 膚憲製艱顧網選衊顧積夢廠淵糧鑰糧繭襯壓廠 (鏇觸築齋餘窪網蓋鹹醖, 1.3 ~ 2.9) 更多
NCT00988858 (Pubmed \| Invest New Drugs) 人工标引	临床2期	非小细胞肺癌二线	55	pemetrexed+LY2603618	(艱衊淵壓積構積製淵構) = 窪範願構窪膚願顧襯獵鹹範糧鑰衊襯餘壓憲範 (選網築壓選鏇網糧醖憲, 3.7 ~ 18.2) 更多	不佳	2016-10-01