Your browser doesn't support javascript.
loading
Rational Design of Novel Allosteric EYA2 Inhibitors as Potential Therapeutics for Multiple Brain Cancers.
Gardner, Lukas; Rossi, John; Armstrong, Brock; Muse, Mia; LaVeck, Alex; Blevins, Melanie A; Zhang, Lingdi; Ford, Heide L; Zhao, Rui; Wang, Xiang.
Afiliación
  • Gardner L; Department of Chemistry, University of Colorado Boulder, 215 UCB, Boulder, CO, 80309.
  • Rossi J; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz School of Medicine, 12801 East 17th Avenue, Mailstop 8101, Aurora, CO, 80045.
  • Armstrong B; Department of Pharmacology, University of Colorado Anschutz School of Medicine, 12800 East 19th Avenue, Mailstop 6126, Aurora, CO, 80045.
  • Muse M; Department of Chemistry, University of Colorado Boulder, 215 UCB, Boulder, CO, 80309.
  • LaVeck A; Department of Chemistry, University of Colorado Boulder, 215 UCB, Boulder, CO, 80309.
  • Blevins MA; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz School of Medicine, 12801 East 17th Avenue, Mailstop 8101, Aurora, CO, 80045.
  • Zhang L; Department of Research & Development, LICORbio, 4647 Superior St, Lincoln, NE, 68504.
  • Ford HL; Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz School of Medicine, 12801 East 17th Avenue, Mailstop 8101, Aurora, CO, 80045.
  • Zhao R; Arnatar Therapeutics, Inc., San Diego, CA, 92121.
  • Wang X; Department of Pharmacology, University of Colorado Anschutz School of Medicine, 12800 East 19th Avenue, Mailstop 6126, Aurora, CO, 80045.
ChemMedChem ; 19(18): e202400179, 2024 Sep 16.
Article en En | MEDLINE | ID: mdl-38861151
ABSTRACT
The Eyes Absent (EYA) family of developmental proteins, often in partnership with the sine oculis (SIX) homeobox proteins, promote cancer metastasis and recurrence in numerous tumor types. In addition to being a transcriptional coactivator, EYA2 is a Tyr phosphatase that dephosphorylates H2AX which leads to repair instead of apoptosis upon DNA damage and ERß which inhibits the anti-tumor transcriptional activity of ERß. The SIX members of the EYA-SIX complex are difficult to target, therefore, we targeted the EYA2 to promote cell death and prevent cancer progression. We conducted structural optimization of a previously discovered allosteric inhibitor of EYA2, 9987, using the combination of in silico modeling, biochemical and cell-based assays. A new series of compounds was developed with significantly improved cellular activity and physiochemical properties desirable for brain targets. Specifically, compound 2 e showed >30-fold improvement in the medulloblastoma cell line D458, relative to 9987, while maintaining potent and selective inhibitory activity against EYA2 Tyr phosphatase activity and a good multiparameter optimization score for central nervous system drugs.
Asunto(s)
Palabras clave
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: Proteínas Nucleares / Diseño de Fármacos / Proteínas Tirosina Fosfatasas / Péptidos y Proteínas de Señalización Intracelular / Antineoplásicos Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Alemania
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: Proteínas Nucleares / Diseño de Fármacos / Proteínas Tirosina Fosfatasas / Péptidos y Proteínas de Señalización Intracelular / Antineoplásicos Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Alemania