WX-554(WX-554) - 药物靶点：MEK1 x MEK2_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

MEK1 x MEK2

作用机制

MEK1抑制剂(双特异性丝裂原活化蛋白激酶激酶1抑制剂)、MEK2抑制剂(双特异性丝裂原活化蛋白激酶激酶2抑制剂)

治疗领域

肿瘤

在研适应症-

非在研适应症

晚期恶性实体瘤肿瘤实体瘤

原研机构

UCB SA

在研机构-

非在研机构

Wilex GmbH Im- u. Export von Investitions- und Verbrauchsgüter

Heidelberg Pharma AGWilex, 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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关联

2

项与 WX-554 相关的临床试验

NCT01859351 / Terminated临床1期

A Phase I Open-label, Dose-escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the PI3K Inhibitor WX-037, Given as a Single Agent and in Combination With the MEK Inhibitor WX-554, in Patients With Solid Tumors

The purpose of this study is to test the safety of escalating doses of the novel PI3K inhibitor WX-037 and to explore its effectiveness in combination with WX-554 which targets mitogen activated protein kinase (MEK1 and MEK2). Preclinical evidence indicates that these two novel compounds could provide targeted inhibition of both pathways to block tumour growth.

开始日期2013-07-01

申办/合作机构

Heidelberg Pharma AG

NCT01581060 / Terminated临床1/2期

A Phase I/II, Open-label, Dose-escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor WX-554 in Patients With Solid Tumours

The aim of part 1 of this study is to determine the optimal biological dose (OBD) and maximum tolerated dose (MTD) for WX-554 and the recommended dose/dose schedules for the chronic treatment in part 2. The aim of part 2 is to further determine the safety and tolerability of chronic treatment with WX-554.

开始日期2012-03-01

申办/合作机构

Heidelberg Pharma AG

100 项与 WX-554 相关的临床结果

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100 项与 WX-554 相关的转化医学

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100 项与 WX-554 相关的专利（医药）

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5

项与 WX-554 相关的文献（医药）

2020-07-07·Current Cancer Drug Targets4区 · 医学

The Therapeutic Potential of MEK1/2 Inhibitors in the Treatment of Gynecological Cancers: Rational Strategies and Recent Progress

4区 · 医学

Review

作者: Khazaei, Majid ; Ghanaatgar-Kasbi, Sadaf ; Hassanian, Seyed Mahdi ; Avan, Amir ; Ferns, Gordon A ; Rastgar-Moghadam, Azam

The mitogen-activated protein kinase (MAPK) pathway is among the key factors in numerous cellular processes involved in tumorigenesis, suggesting it as a potential therapeutic target in gynecological cancer. MAPKs connect gene expression pathways and external stimulations. They include a network consisting of Ras, Raf or MAP3K, MEK or MAP2K, ERK or MAPK. Among these, MEK is an attractive molecular target of novel cancer therapeutics as it joints upstream activators and their corresponding downstream targets. MEK inhibitors were among the first inhibitors of the MAPK pathway entering into clinical trials. Several drugs have recently been developed as MEK inhibitors. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity to treat this malignancy and captured much attention in the past decade. Here, we summarize the role of MAPK/MEK/ERK pathway in the pathogenesis of gynecological cancer, with particular emphasis on MEK inhibitors in clinical settings, including PD-0325901, Selumetinib, Cobimetinib, Refametinib, Trametinib, Pimasertib, MEK162 and WX-554 in gynecologic cancers.

2016-12-01·Cancer Chemotherapy and Pharmacology4区 · 医学

Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037

4区 · 医学

Article

作者: Thomas, Huw D ; Payne, Andrew C ; Schmalix, Wolfgang A ; Bevan, Paul ; Kevorkian, Lara ; Maxwell, Ross J ; Newell, David R ; Haagensen, Emma J ; Allen, Rodger A

PURPOSETumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.METHODSIn vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.RESULTSThe combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.CONCLUSIONThese studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.

2016-11-01·European Journal of Cancer1区 · 医学

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

1区 · 医学

Article

作者: David Jamieson ; Melanie J. Griffin ; Richard H. Wilson ; Nicola Cresti ; Paul Bevan ; Alastair Greystoke ; Yvette Drew ; T. R. Jeffery Evans ; Ruth Plummer ; Vicky Coyle ; Karen Swales ; Udai Banerji ; Rodger Allen ; Lisa Rodgers ; Carola Mala ; Alan V. Boddy ; Markus Buerkle ; Emma J. Dean ; Julieann Sludden ; Mark Merriman ; Alan Anthoney ; Malcolm R. Ranson

PURPOSEWe performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.EXPERIMENTAL DESIGNPatients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.RESULTSForty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.CONCLUSIONSWX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

100 项与 WX-554 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
晚期恶性实体瘤	临床2期	英国	Heidelberg Pharma AG	2012-03-01
实体瘤	临床2期	英国	Wilex GmbH Im- u. Export von Investitions- und Verbrauchsgüter	2012-03-01
肿瘤	临床2期	德国	Wilex, Inc.	-