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Ref Type Journal Article
PMID (19383820)
Authors Sabbatini P, Rowand JL, Groy A, Korenchuk S, Liu Q, Atkins C, Dumble M, Yang J, Anderson K, Wilson BJ, Emmitte KA, Rabindran SK, Kumar R
Title Antitumor activity of GSK1904529A, a small-molecule inhibitor of the insulin-like growth factor-I receptor tyrosine kinase.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 15
Issue 9
Date 2009 May 01
URL
Abstract Text Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers.Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated.GSK1904529A selectively inhibits IGF-IR and IR with IC(50)s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity.GSK1904529A is a promising candidate for therapeutic use in IGF-IR-dependent tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
GSK1904529A GSK1904529A 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GSK1904529A IGF-1R Inhibitor 17 GSK1904529A inhibits IGF-IR and IR, resulting in cell-cycle arrest and decreased tumor growth (PMID: 19383820, PMID: 28572530).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Ewing sarcoma not applicable GSK1904529A Preclinical - Cell culture Actionable In a preclinical study, Ewing's sarcoma cells were sensitive to GSK1904529A in culture, resulting in decreased cell viability (PMID: 19383820). 19383820
Unknown unknown pancreatic adenocarcinoma not applicable GSK1904529A Preclinical - Cell line xenograft Actionable In a preclinical study, GSK1904529A treatment resulted in inhibition of tumor growth by 52% in xenograft models of pancreas adenocarcinoma (PMID: 19383820). 19383820
Unknown unknown breast cancer not applicable GSK1904529A Preclinical - Cell culture Actionable In a preclinical study, GSK1904529A treatment resulted in decreased cell viability of breast cancer cells in culture (PMID: 19383820). 19383820
Unknown unknown multiple myeloma not applicable GSK1904529A Preclinical - Cell culture Actionable In a preclinical study, multiple myeloma cells were sensitive to GSK1904529A in culture, resulting in decreased cell viability (PMID: 19383820). 19383820