title: 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.
authors.affiliation: Diabetes and Endocrine Research University of California, San Francisco/Mt. Zion Medical Center, Box 1616, San Francisco, CA 94143-1616, USA.
authors.forename: Karissa L
authors.initials: KL
authors.lastname: Gable
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Cristina
authors.initials: C
authors.lastname: Penaranda
authors.forename: Marianna
authors.initials: M
authors.lastname: Zavodovskaya
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campbell
authors.forename: Margaret
authors.initials: M
authors.lastname: Lobo
authors.forename: Louise
authors.initials: L
authors.lastname: Robinson
authors.forename: Steven
authors.initials: S
authors.lastname: Schow
authors.forename: John A
authors.initials: JA
authors.lastname: Kerner
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
mesh_terms: D000634:Aminoquinolines / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014508:Urea / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; C569479:PQ 401; D010671:Phenylurea Compounds; D014508:Urea; D017526:Receptor, IGF Type 1; D020169:Caspases