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GDC-0973 (XL518)

This drug has been in a Phase I trial as a single agent and is now entering a combination trial.  Originally under development by Exelixis as XL518, it is now being developed by Genentech as GDC-0973.

Mode of action:  orally administered inhibitor of MEK1 (also called MAPK kinase 1)

Definition from NCI Drug Dictionary:
MEK inhibitor XL518  is an orally active small molecule, targeting mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1), with potential antineoplastic activity. MEK inhibitor XL518 specifically binds to and inhibits the catalytic activity of MEK1, resulting in inhibition of extracellular signal-related kinase 2 (ERK2) phosphorylation and activation and decreased tumor cell proliferation. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a B-RAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases

Manufacturer:

Currently under development by Genentech
Originally under development by Exelixis

Information at Exelixis website:
http://www.exelixis.com/pipeline_xl518.shtml

information at the Genentech website:
http://www.gene.com/gene/pipeline/status/oncology/mek/

Clinical trials relevant to GIST patients:

NCT00996892: A Study Evaluating the Safety, Tolerability and Pharmacokinetics of GDC-0973 in Combination With GDC-0941 When Administered Daily in Patients With Locally Advanced or Metastatic Solid Tumors
Phase I   (not yet open for recruitment)

NCT00467779  Study of GDC-0973/XL518 in Patients With Solid Tumors
Phase I trial recruiting

Available publications or presentations about this drug:

ASCO 2008 presentation:
A phase 1 dose-escalation study of XL518, a potent MEK inhibitor administered orally daily to subjects with solid tumors.  Abstract No: 14585
Citation: J Clin Oncol 26: 2008 (May 20 suppl; abstr 14585)
Author(s): L. S. Rosen, P. Galatin, J. M. Fehling, I. Laux, M. Dinolfo, J. Frye, D. Laird, B. I. Sikic 


Johnston, S (2007). XL518, a potent, selective orally bioavailable MEK1 inhibitor, down-regulates the Ras/Raf/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in preclinical models. 19th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (San Francisco, CA, Oct 22-26). (Abstract C209).

Kohno M, Pouyssegur J (2006). Targeting the ERK signaling pathway in cancer therapy. Ann Med 38(3):200-11.  PMID: 16720434



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