Your browser doesn't support javascript.
loading
Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer.
Luxenburger, Andreas; Bougen-Zhukov, Nicola; Fraser, Michael G; Beetham, Henry; Harris, Lawrence D; Schmidt, Dorian; Cameron, Scott A; Guilford, Parry J; Evans, Gary B.
Afiliación
  • Luxenburger A; Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
  • Bougen-Zhukov N; Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin 9016, New Zealand.
  • Fraser MG; Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
  • Beetham H; Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin 9016, New Zealand.
  • Harris LD; Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
  • Schmidt D; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, Germany.
  • Cameron SA; Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
  • Guilford PJ; Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin 9016, New Zealand.
  • Evans GB; Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
J Med Chem ; 64(24): 18114-18142, 2021 12 23.
Article en En | MEDLINE | ID: mdl-34878770
Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attractive targets for drug development. Recently, SLEC-11 (1) emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize 1. Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1-/-). Among the 26 compounds with greater cytotoxicity, AL-GDa62 (3) was four-times more potent and more selective than 1 with an EC50 ratio of 1.6. Furthermore, 3 preferentially induced apoptosis in CDH1-/- cells, and Cdh1-/- mammary and gastric organoids were significantly more sensitive to 3 at low micromolar concentrations. Thermal proteome profiling of treated MCF10A-CDH1-/- cell protein lysates revealed that 3 specifically inhibits TCOF1, ARPC5, and UBC9. In vitro, 3 inhibited SUMOylation at low micromolar concentrations.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Descubrimiento de Drogas / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Descubrimiento de Drogas / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Nueva Zelanda Pais de publicación: Estados Unidos