Lapatinib

Boyd, B.; Bozzo, J.; Castañer, J.; Bayés, M.

doi:10.1358/dof.2005.030.12.946811

Cited by 8 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The free base of AZD8931 is disclosed in PCT patent publication number WO2005/028469 and can be prepared using the methods described therein. The synthesis of gefitinib and lapatinib has been previously described (14,15).…”

Section: Methodsmentioning

confidence: 99%

AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer

Hickinson

Klinowska

Speake

et al. 2010

Clinical Cancer Research

107

View full text Add to dashboard Cite

Purpose: To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo.Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors.Results: In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC 50 , 4 nmol/L), erbB2 (IC 50 , 3 nmol/L), and erbB3 (IC 50 , 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation.Conclusions: AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159-69. ©2010 AACR.The erbB receptor family is composed of four related receptor tyrosine kinases [epidermal growth factor receptor (EGFR, erbB1), erbB2 (human epidermal growth factor receptor 2, HER2), erbB3 (HER3), and erbB4 (HER4)]. ErbB2 lacks ligand-binding capacity and erbB3 is intrinsically inactive as a kinase. There are two main ligand classes: the first bind specifically to EGFR whereas the second includes the neu differentiation factors, or heregulins, which bind erbB3 and erbB4 (1). In cancer, activation of erbB2 may arise by (a) receptor overexpression inducing homodimerization and (b) receptor heterodimerization with another family member, of which erbB3 is considered to be the preferred and most oncogenic partner (2).Homodimerization and/or heterodimerization of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival (3, 4). The deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and has been described in many human cancers, in...

show abstract

Section: Methodsmentioning

confidence: 99%

AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer

Hickinson

Klinowska

Speake

et al. 2010

Clinical Cancer Research

107

View full text Add to dashboard Cite

show abstract

“…Current approved drugs for the treatment of cancers driven by the HER family of proteins are either monoclonal antibodies such as trastuzumab (directed at HER-2) or cetuximab (directed at HER-1) or small-molecule tyrosine kinase inhibitors such as gefitinib and erlotinib (HER-1 kinase inhibitors) and lapatinib (dual HER-2 kinase and HER-1 kinase inhibitor; refs. 3,10,16,17). Several other monoclonal antibodies and tyrosine kinase inhibitors directed toward the HER family proteins are in clinical trials (3,16,17).…”

Section: Introductionmentioning

confidence: 99%

“…3,10,16,17). Several other monoclonal antibodies and tyrosine kinase inhibitors directed toward the HER family proteins are in clinical trials (3,16,17).…”

Section: Introductionmentioning

confidence: 99%

Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activityin vitroand in human tumor xenografts

Sarup¹,

Pei²,

Turin³

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Lapatinib (Tykerb ® , 15), ein dualer EGFR/HER2-Inhibitor, ist die jüngste Verbindung aus dieser Reihe [30]. Die GlaxoSmithKline-Substanz wurde 2007 von der FDA zur Second-line-Therapie fortgeschrittener oder metastasierter Mammakarzinome zugelassen, bei denen eine Überexpres-…”

Section: Erlotinibunclassified

Die kurze Geschichte der Proteinkinase‐Inhibitoren. Jung, kompetitiv, erfolgreich

Kunick

Egert-Schmidt

2008

Pharmazie in unserer Zeit

View full text Add to dashboard Cite

Obwohl Proteinkinasen vielfältig an pathophysiologischen Vorgängen beteiligt sind, wurde die Option, durch eine Hemmung dieser Enzyme therapeutisch einzugreifen, lange unterschätzt. In der Grundlagenforschung wurden Anfang der 1980er Jahre bahnbrechende Erkenntnisse zur Struktur, Funktion und Bedeutung der Proteinkinasen gewonnen. Viele der forschenden Pharmaunternehmen machten daraufhin die Suche nach Proteinkinase‐Inhibitoren zu einem Forschungsschwerpunkt.

show abstract

Lapatinib

Cited by 8 publications

References 0 publications

AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer

AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer

Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activityin vitroand in human tumor xenografts

Die kurze Geschichte der Proteinkinase‐Inhibitoren. Jung, kompetitiv, erfolgreich

Contact Info

Product

Resources

About