Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth

Abstract

In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti–breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 μmol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 μmol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 μmol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 μmol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 μmol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers. [Mol Cancer Ther 2006;5(4):1079–86]

Lkb1/Stk11 regulation of mTOR signaling controls the transition of chondrocyte fates and suppresses skeletal tumor formation

“…In contrast, GDC-0449 and XAV939, inhibitors of Hh and Wnt signaling [Wnt signaling is linked to chondrocyte maturation (16)], respectively, had no effect (Fig. 4 D and E) (17)(18)(19)(20). Furthermore, although GDC-0449 abolished chondrocyte proliferation in control skeletal elements in vivo, GDC-0449 failed to block EdU incorporation into Lkb1 mutant chondrocytes (Fig.…”

Insulin-like Growth Factor 1-mediated Hyperthermia Involves Anterior Hypothalamic Insulin Receptors

“…The signaling mechanism of the IGF-1 on POA neurons was examined by pretreatment with the IGF-1R tyrosine kinase inhibitor PQ401 that inhibits IGF-1R autophosphorylation (48). Pretreatment with PQ401 before IGF-1 (10 ng in 0.5 l), both administered to the POA 30 min apart, showed significant attenuation of the IGF-1-induced increase in core body temperature (p Ͻ 0.05) (Fig.…”

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

“…A chemical library was employed in screening assays for IGF-1R inhibitory potency in MCF-7 breast cancer cells to give a diarylurea hit, and the subsequent diarylurea libraries screening assays led to the identification of 41 (PQ401) [65]. The compound inhibited cellular IGF-1R autophosphorylation at an IC 50 Currently, the same group explored SAR around the previously characterized lead 41, and several analogues were identified with improved activity (IC 50 = 3~5 M) [66].…”