依克立达(Elacridar) - 药物靶点：ABCG2 x P-gp_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Elacridar hydrochloride (USAN)

+ [6]

靶点

ABCG2 x P-gp

作用方式

抑制剂

作用机制

ABCG2抑制剂(ATP结合盒转运子亚家族G成员2抑制剂)、P-gp抑制剂(P-糖蛋白-1抑制剂)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

GSK Plc

在研机构

Chiba University

非在研机构

GSK Plc

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C34H33N3O5

InChIKeyOSFCMRGOZNQUSW-UHFFFAOYSA-N

CAS号143664-11-3

关联

2

项与依克立达相关的临床试验

NL-OMON38922

/ CompletedN/AIIT

Pharmacokinetic study of a new formulation of elacridar - Pharmacokinetic study of a new formulation of elacridar

开始日期2013-10-25

申办/合作机构-

EUCTR2010-020759-30-AT

/ Not yet recruitingN/AIIT

A pilot study to assess [11C]elacridar and [11C]tariquidar as two positron emission tomography radiotracers for visualization of P-glycoprotein in humans. - [11C]inhibitors

开始日期2010-11-03

申办/合作机构

Medizinische Universität Graz

100 项与依克立达相关的临床结果

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100 项与依克立达相关的转化医学

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100 项与依克立达相关的专利（医药）

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690

项与依克立达相关的文献（医药）

2025-04-01·Journal of Molecular Biology

Conversion of Human Multidrug Transporter P-glycoprotein (ABCB1) from Drug Efflux to Uptake Pump: Evidence for a Switch Region Modulating the Direction of Substrate Transport

作者: Durell, Stewart R. ; Ranganathan, Nandhini ; Ambudkar, Suresh V. ; Ahmed, Shafaq ; Sajid, Andaleeb ; Guha, Rajan ; Murakami, Megumi

The multidrug transporter P-glycoprotein (P-gp), is pivotal in exporting various chem. dissimilar amphipathic compounds including anti-cancer drugs, thus causing multidrug resistance during cancer treatment.P-gp is composed of two transmembrane domains (TMDs), each containing six homologous transmembrane helixes (TMHs).Among these helixes, TMH 6 and 12 align oppositely, lining a drug-binding pocket in the transmembrane region which acts as a pathway for drug efflux.Previously, specific mutations within TMH 6 and 12 resulted in loss of substrate efflux and altered the transport direction from efflux to uptake for some substrates.This suggested a regulatory switch that governs the direction of transport.The authors sought to elucidate the mechanism of switch region modulation of the uptake function by engineering several mutants via substituting specific residues in TMH 6 and 12.The alanine substitution of four residues (V974, L975, V977, and F978) within the upper region of TMH 12, along with three residues (V334, F336, and F343) within TMH 6, was sufficient to convert P-gp from an efflux to an uptake pump.Addnl. mutagenesis of the residues in the middle region of TMH 12 revealed that the uptake function, like efflux, is reversible.Further studies, including mol. dynamics simulations, revealed that the switch region appears to act during the substrate translocation step.The authors propose that the switch region in TMH 6 and 12, which modulates the direction of transport by P-gp, provides a novel approach to selectively target P-gp-expressing cancer cells.

2025-01-09·Journal of Medicinal Chemistry

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives

Article

作者: Sopper, Sieghart ; Puhr, Martin ; Schoepf, Anna M. ; Heidegger, Isabel ; Federspiel, Martin ; Pircher, Andreas ; Salcher, Stefan ; Wolf, Dominik ; Hotze, Madlen ; Kwiatkowski, Marcel ; Gust, Ronald ; Gebhart, Maximilian

The present structure-activity relationship study investigates the development of novel chemosensitizers targeting therapy-resistant cancer stem cells (CSCs). We used 4'-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from the angiotensin II type 1 receptor blocker telmisartan, as a lead structure, demonstrating that the biphenyl moiety is essential for chemosensitizing activity. Introducing a methyl carboxylate or carboxamide instead of the COOH-group significantly enhanced this effect, leading to the development of highly potent compounds. These novel, noncytotoxic chemosensitizers effectively target CSCs and overcome drug resistance by interfering with CSC persistence mechanisms─hyperactivated STAT5 signaling and increased drug transporter activity─with demonstrated efficacy in leukemia, ovarian, and prostate cancers. The carboxamide of telmisartan (telmi-amide, 7c) significantly reduced tumor growth in an imatinib-resistant leukemia xenograft model, both as monotherapy and combined with imatinib, showing promising oral bioavailability and tolerability. In summary, telmisartan derivatives act as effective chemosensitizers and offer an innovative strategy for targeting CSCs in various malignant diseases.

2024-12-01·European Journal of Medicinal Chemistry

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect

Article

作者: Zhao, Jiangyan ; Tan, Zhoupeng ; Gu, Xiaoke ; Li, Zheng ; Yuan, Weiqun ; Feng, Hao ; Sun, Shuang ; Niu, Mingshan ; Qiu, Jingying ; Wu, Yiqing ; Zeng, Meifeng

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

100 项与依克立达相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D03968	-	-	DB04881

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
肿瘤	临床前	欧洲	-	-
肿瘤	临床前	-	GSK Plc	-
肿瘤	临床前	美国	-	-
肿瘤	临床前	加拿大	-	-

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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


P10.21.A (EANO2023)	N/A	脑癌	-	Elacridar	鑰蓋窪網憲積艱糧網網(壓顧構醖鹽構選獵齋築) = 鏇廠淵簾鏇簾蓋構衊鹽蓋襯膚簾願顧憲鹽繭製 (膚繭築獵醖廠壓窪壓鬱 )	-	2023-09-08
EANM2016	N/A	P-glycoprotein	3	Elacridar	艱鹽憲鏇遞淵膚範簾願(衊糧膚壓壓築範網壓網) = 選願遞醖範醖蓋膚遞衊鏇廠壓廠繭鹽膚糧製繭 (鹹遞蓋鬱憲壓構艱獵窪 )	积极	2016-09-21
EANM2016	N/A	P-glycoprotein	3	High-dose Erlotinib	艱鹽憲鏇遞淵膚範簾願(衊糧膚壓壓築範網壓網) = 憲廠積範衊製鑰鏇獵淵鏇廠壓廠繭鹽膚糧製繭 (鹹遞蓋鬱憲壓構艱獵窪 )	积极	2016-09-21
SNMMI2016	N/A	-	-	High dose erlotinib	廠範網廠齋壓積鏇網夢(憲糧壓壓蓋衊廠範壓鏇) = 鬱夢製觸淵鹹鑰鹽製願鏇膚網廠壓鬱憲簾廠顧 (餘壓壓積願蓋衊壓窪餘, 0.03)	-	2016-05-24
SNMMI2016	N/A	-	-	Elacridar	廠範網廠齋壓積鏇網夢(憲糧壓壓蓋衊廠範壓鏇) = 糧衊觸鬱構淵繭齋積選鏇膚網廠壓鬱憲簾廠顧 (餘壓壓積願蓋衊壓窪餘, 0.35)	-	2016-05-24
ASCO2004	临床1期	晚期癌症	23	Topotecan 2 mg + Elacridar 100 mg	廠選艱網觸獵鹽蓋鹽襯(觸範鹹觸餘鑰艱衊糧餘) = DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. 鹹淵遞顧簾齋憲鹹願憲 (選鹹遞簾憲繭網襯鹽憲 ) 更多	-	2004-07-15