American Association for Cancer Research
Browse
10780432ccr082530-sup-supplementary_data.pdf (343.88 kB)

Supplementary Data from Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Download (343.88 kB)
journal contribution
posted on 2023-03-31, 15:46 authored by Peter Sabbatini, Jason L. Rowand, Arthur Groy, Susan Korenchuk, Qi Liu, Charity Atkins, Melissa Dumble, Jingsong Yang, Kelly Anderson, Brian J. Wilson, Kyle A. Emmitte, Sridhar K. Rabindran, Rakesh Kumar
Supplementary Data from Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

History

ARTICLE ABSTRACT

Purpose: 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.Experimental Design: 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.Results: GSK1904529A selectively inhibits IGF-IR and IR with IC50s 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.Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IR–dependent tumors.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC