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 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/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 micromol/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.
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ABSTRACT: The insulin-like family is not only an important regulatory factor for animal growth, development, and metabolism, but also a mediator for initiating growth activity of growth hormone. It plays an important role in transferring transmembrane information and regulating cell function by binding to tyrosine kinase receptors (insulin receptors). To better understand the role of insulin-related peptide receptor (Pfirr) on the developmental regulation in Pinctada fucata, 5.326 kb encoding cDNAs for Pfirr have been cloned and functionally characterized. Pfirr displays significant homologies to Crassostrea gigas, and exhibits all the typical features of insulin receptors and tyrosine kinase domain structure, both of which are typical for the protein family sharing high similarity to other orthologs. Real-time PCR analyses show that Pfirr widely expresses in tissues and developmental stages of P. fucata. Expression of Pfirr mRNAs at different developmental stages (polar body stage, the trocophore stage and D-shaped larva stage) following treatment with agonist IGF-I(1, 2, 4 and 8 μM/L) and antagonist PQ401 (5, 15, 25, 50 and 100 μM/L) indicated that Pfirr may be involved in regulating the development of embryos in P. fucata. These results clearly demonstrate Pfirr is involved in regulating developmental process in P. fucata.Aquaculture 09/2013; s 408–409:118–127. DOI:10.1016/j.aquaculture.2013.05.038 · 1.83 Impact Factor
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ABSTRACT: A series of substituted N-(quinolin-4-yl)ethanediamine phenyl urea derivatives of biological interest were prepared by sequential quinoline synthesis, chlorination, and substitution reaction followed by reaction of resulting amine with different aryl isocyanates. All synthesized compounds (1–13) were screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation study revealed that among all the compounds screened, compounds 4 and 6 were found to have promising anti-inflammatory activity (up to 78–71 % TNF-α and 96–90 % IL-6 inhibitory activity) at a higher concentration of 10 μM with reference to standard dexamethasone (72 % TNF-α and 86 % IL-6 inhibitory activities at 1 μM). Compounds 6, 8, 10, and 11 overall exhibited promising antimicrobial activity at MIC values ranging from 10 to 30 μg/mL against all the selected pathogenic bacteria and fungi.Medicinal Chemistry Research 03/2012; 22(3). DOI:10.1007/s00044-012-0144-5 · 1.61 Impact Factor
Conference Paper: Nonlinear gain-scheduled control design using set-valued methods[Show abstract] [Hide abstract]
ABSTRACT: This paper presents a nonlinear gain-scheduled control design approach using set-valued methods. Previous results for set-valued methods for linear parameter-varying (LPV) systems are applied to nonlinear systems with quasi-LPV representations. The proposed design approach differs from traditional gain-scheduling in several aspects: 1) linearization errors are accommodated as linear state-dependent disturbances; 2) constraints on system states and controls are specified; and 3) rates of transitions among operating regions are explicitly addressed. As a consequence, even “local” set point designs are nonlinear. Nonlinear parameter-dependent state feedback which is guaranteed to achieve constrained regulation, is constructed by solving several linear programsAmerican Control Conference, 1998. Proceedings of the 1998; 07/1998