title: Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).
abstract: The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3-5 microM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding.
authors.affiliation: Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: William
authors.initials: W
authors.lastname: Engen
authors.forename: Terrence E
authors.initials: TE
authors.lastname: O'Brien
authors.forename: Brendan
authors.initials: B
authors.lastname: Kelly
authors.forename: Jacinda
authors.initials: J
authors.lastname: Do
authors.forename: Liezel
authors.initials: L
authors.lastname: Rillera
authors.forename: Lance K
authors.initials: LK
authors.lastname: Stapleton
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D017451:Receptors, Somatomedin; D014508:Urea; C001920:4-aminoquinoline