Delving into the Latest Updates on WX-554 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

MEK1 inhibitors(Dual specificity mitogen-activated protein kinase kinase 1 inhibitors), MEK2 inhibitors(Dual specificity mitogen-activated protein kinase kinase 2 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmNeoplasmsSolid tumor

Originator Organization

UCB SA

Active Organization-

Inactive Organization

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

Heidelberg Pharma AGWilex, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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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.

Start Date01 Jul 2013

Sponsor / Collaborator

Heidelberg Pharma AG

NCT01581060 / TerminatedPhase 1/2

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.

Start Date01 Mar 2012

Sponsor / Collaborator

Heidelberg Pharma AG

100 Clinical Results associated with WX-554

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100 Translational Medicine associated with WX-554

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100 Patents (Medical) associated with WX-554

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5

Literatures (Medical) associated with WX-554

07 Jul 2020·Current Cancer Drug TargetsQ4 · MEDICINE

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

Q4 · MEDICINE

Review

Author: 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.

01 Dec 2016·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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.

01 Nov 2016·European Journal of CancerQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with WX-554

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	GB	Heidelberg Pharma AG	01 Mar 2012
Solid tumor	Phase 2	GB	Wilex GmbH Im- u. Export von Investitions- und Verbrauchsgüter	01 Mar 2012
Neoplasms	Phase 2	DE	Wilex, Inc.	-