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

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 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. Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IR^dependent tumors.

GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers

“…The transient increase in blood glucose, especially in the glucose tolerance test, clearly suggests the perturbation of insulin signaling. Similar results were observed with the structurally distinct IGF-IR/IR inhibitors GSK1904529A (22) and NVP-AEW541 (24). The increase in insulin levels provides a potential explanation for the minimal change in blood glucose; however, the sustained hyperinsulinemia in mice treated for 23 days, compared with 8 days, suggests that caution is warranted with chronic dosing.…”

“…A structurally distinct IGF-IR-selective inhibitor previously described, GSK1904529A, showed similar potent activity against IGF-IR and IR, but lacked activity against ALK (21,22). Both compounds inhibited IGF-IR signaling in cells, although GSK1904529A seemed to be more potent than GSK1838705A.…”

Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

“…Increased expression of IGF-1, IGF-2 and/or their corresponding receptor, IGF-1R, has been shown in a broad range of tumors and increased levels of circulating IGF-1 are associated with colon, prostate, breast, lung, and bladder cancers (5,7). Given its pleiotropic role in these tumor types, several approaches have been taken to inhibit IGF-1R signaling, including RNA antisense (8,9), anti-IGF-1R-blocking antibodies (10), dominant-negative IGF-1R (11), and small-molecule inhibitors (12)(13)(14)(15)(16).…”

IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

“…We also demonstrate in the Met1 ERa low luminal B breast cancer model that, despite enhanced serum insulin levels, reduced circulating levels of IGF1 decrease Akt signaling (pAkt and cyclin D1) and EMT and chemokine gene expression, all of which regulate tumor growth, progression, and/or metastatic potential in other cancer models (Ahmad et al 1999, Mira et al 1999, 2001, Akekawatchai et al 2005, Singh et al 2009, Wu et al 2010, Durfort et al 2012. Pharmacological inhibitors of the IGF1 pathway effectively diminish breast tumor growth in several preclinical models of breast cancer (Maloney et al 2003, Haluska et al 2006, Gualberto & Pollak 2009, Sabbatini et al 2009, Sun et al 2011. Unfortunately, clinical application has been limited by safety concerns (Gualberto & Pollak 2009) and efficacy due to high phosphorylation of IGF1/insulin receptors in all breast cancer subtypes (Law et al 2008).…”