Itarnafloxin(Itarnafloxin) - 药物靶点：G4_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Quarfloxin

+ [1]

靶点

G4

作用机制

G4抑制剂(G-四链体抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病

在研适应症-

非在研适应症

晚期恶性实体瘤类癌难治性慢性淋巴细胞白血病+ [3]

原研机构

Cylene Pharmaceuticals, Inc.

在研机构-

非在研机构

TetraGene LLC

Cylene Pharmaceuticals, Inc.

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-

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结构

分子式C35H33FN6O3

InChIKeyWOQIDNWTQOYDLF-CGAIIQECSA-N

CAS号865311-47-3

关联

4

项与 Itarnafloxin 相关的临床试验

NCT00780663 / Completed临床2期

A Phase 2, Multi-Center, Open Label Study Evaluating the Efficacy and Safety of Quarfloxin in Patients With Low to Intermediate Grade Neuroendocrine Carcinoma

This is a Phase 2, open-label, multicenter, efficacy and safety study of quarfloxin in patients with low or intermediate grade neuroendocrine cancer. The purpose of this study is to evaluate the rate of clinical benefit response to quarfloxin treatment including the reduction in secretory symptoms of flushing and/or diarrhea or the reduction quantifiable hormones or other biochemical tumor markers.

开始日期2008-10-01

申办/合作机构

Cylene Pharmaceuticals, Inc.

NCT00955292 / Terminated临床1期

A Phase I, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Quarfloxin Administered Intravenously Weekly for Three Weeks of a Four Week Cycle in Patients With Advanced Solid Tumors or Lymphomas

This phase 1 study of quarfloxin (CX-3543) is designed to test the safety, tolerability, and highest safe dose of this drug when administered intravenously weekly for three weeks of a four week cycle in patients with advanced solid tumors.

开始日期2007-07-01

申办/合作机构

Cylene Pharmaceuticals, Inc.

NCT00485966 / Withdrawn临床2期

A Phase 2, Multi-Center, Open Label Study Evaluating Clinical Efficacy, Safety, and Pharmacodynamic Effects of Quarfloxacin (CX-3543) in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia (B-CLL)

This is a Phase 2, open-label, multicenter, efficacy, safety, and pharmacodynamic study of CX-3543 in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL).

开始日期2007-06-01

申办/合作机构

Cylene Pharmaceuticals, Inc.

100 项与 Itarnafloxin 相关的临床结果

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100 项与 Itarnafloxin 相关的转化医学

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100 项与 Itarnafloxin 相关的专利（医药）

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15

项与 Itarnafloxin 相关的文献（医药）

2024-06-17·ChemBioChem

Systematic Evaluation of Benchmark G4 Probes and G4 Clinical Drugs using three Biophysical Methods: A Guideline to Evaluate Rapidly G4‐Binding Affinity

Article

作者: Teulade‐Fichou, M.‐P. ; Beauvineau, C. ; Lavergne, T. ; Dejeu, J. ; Laigre, E. ; Defrancq, E. ; Bonnet, H. ; Verga, D.

AbstractG‐quadruplex DNA structures (G4) are proven to interfere with most genetic and epigenetic processes. Small molecules binding these structures (G4 ligands) are invaluable tools to probe G4‐biology and address G4‐druggability in various diseases (cancer, viral infections). However, the large number of reported G4 ligands (>1000) could lead to confusion while selecting one for a given application. Herein we conducted a systematic affinity ranking of 11 popular G4 ligands vs 5 classical G4 sequences using FRET‐melting, G4‐FID assays and SPR. Interestingly SPR data globally align with the rankings obtained from the two semi‐quantitative assays despite discrepancies due to limits and characteristics of each assay. In the whole, PhenDC3 emerges as the most potent binder irrespective of the G4 sequence. Immediately below PDS, PDC‐360A, BRACO19, TMPyP4 and RHPS4 feature strong to medium binding again with poor G4 topology discrimination. More strikingly, the G4 drugs Quarfloxin, CX5461 and c‐PDS exhibit weak affinity with all G4s studied. Finally, NMM and Cu‐ttpy showed heterogeneous behaviors due, in part, to their physicochemical particularities poorly compatible with screening conditions. The remarkable properties of PhenDC3 led us to propose its use for benchmarking FRET‐melting and G4‐FID assays for rapid G4‐affinity evaluation of newly developed ligands.

2023-12-01·International Journal for Parasitology: Drugs and Drug Resistance

Effects of the G-quadruplex-binding drugs quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum

Article

作者: Cicuta, Pietro ; Craven, Holly M ; Blagborough, Andrew M ; Merrick, Catherine J ; Nettesheim, Guilherme

Plasmodium falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to most drugs, including the current frontline treatments, so new therapeutic targets are needed. Our previous work on guanine quadruplexes (G4s) in the parasite's DNA and RNA has highlighted their influence on parasite biology, and revealed G4 stabilising compounds as promising candidates for repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive.

2022-12-01·Bioorganic & Medicinal Chemistry Letters

A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)

Review

作者: Xu, Hong ; Hurley, Laurence H

CX-3543 (Quarfloxin) and CX-5461 (Pidnarulex) were originally derived from a group of fluoroquinolones that were shown to have dual topoisomerase II (Top2) and G-quadruplex (G4) interactions, and QQ58 was the starting structure for their design. Quarfloxin was initially shown to inhibit c-MYC mRNA expression. Studies at Cylene Pharmaceuticals showed that the primary mechanism of action of Quarfloxin is due to displacement of nucleolin from quadruplexes on the non-template strand of rDNA, causing rapid redistribution of nucleolin from nucleoli, inhibition of rRNA synthesis, and apoptotic death in cancer cells. At Cylene a follow-up compound to Quarfloxin, named Pidnarulex (CX-5461), was optimized for targeting RNA Pol 1. Significantly, in more recent work published in Proc Natl Acad Sci USA and Cell in 2020 and in eLIFE and Nat Comm in 2021, it has been shown that the real molecular target for Pidnarulex is Top2 at transcribed regions containing G4s, rather than RNA Pol 1. These results support the original design strategy published in Mol Cancer Ther in 2001, which was to rationally design a G4-targeting drug (QQ58) starting from a fluoroquinolone duplex-targeting Top2 poison (A-62176) that had good drug-like properties. A very important breakthrough was realized when homologous recombination (HR) was found to be important in the repair of DNA damage caused by G4-interactive compounds, suggesting that a synthetic lethal approach might be useful in identifying cancer patients sensitive to these agents. Through use of an unbiased screen, this mechanistic insight was shown to directly apply to Cylene compounds, which were found to induce DNA damage and to be dependent on BRCA1/2-mediated HR and the DNA-PK-mediated nonhomologous end-joining (NHEJ) pathway for damage repair. To evaluate how this mechanistic insight involving a synthetic lethal approach might be applied clinically, a recent Canadian Phase I clinical trial with Pidnarulex in breast and ovarian cancer patients with known BRCA1/2 germline mutations was carried out. Because of the G4 stabilizer function of Pidnarulex, patient populations that responded well to this compound were identified: they are cancer patients with BRCA1/2 deficiency or deficiency in other DNA damage response pathways. Clinically observed resistance to Pidnarulex resulted from reversion to WT BRCA2 and PALB2 ("partner and localizer of BRCA2," because it partners with another gene, called BRCA2), thus providing strong evidence for the underlying synthetic lethal hypothesis proposed for G4-targeting compounds that cause DNA damage.

100 项与 Itarnafloxin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06638

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
类癌	临床2期	美国	Cylene Pharmaceuticals, Inc.	2008-10-01
难治性慢性淋巴细胞白血病	临床2期	美国	Cylene Pharmaceuticals, Inc.	2007-06-01
晚期恶性实体瘤	临床2期	美国	Cylene Pharmaceuticals, Inc.	2005-07-01
淋巴瘤	临床2期	美国	Cylene Pharmaceuticals, Inc.	2005-07-01
慢性淋巴细胞白血病	临床2期	-	TetraGene LLC	-
神经内分泌癌	药物发现	美国	Cylene Pharmaceuticals, Inc.	2008-10-01

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临床结果

适应症

分期

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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


ASCO2007	临床1期	HR阳性/HER2低表达实体瘤	-	CX-3543	膚範繭顧齋選齋膚簾鏇(淵獵壓繭遞餘膚製範範) = No drug related serious adverse events (SAEs) were encountered 憲糧廠選構鬱選襯繭鏇 (淵膚獵壓遞觸鬱餘襯淵 ) 更多	-	2007-06-20