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Identification of Novel GANT61 Analogs with Activity in Hedgehog Functional Assays and GLI1-Dependent Cancer Cells.
Abu Rabe, Dina; Chdid, Lhoucine; Lamson, David R; Laudeman, Christopher P; Tarpley, Michael; Elsayed, Naglaa; Smith, Ginger R; Zheng, Weifan; Dixon, Maria S; Williams, Kevin P.
Afiliación
  • Abu Rabe D; INBS PhD Program, North Carolina Central University, Durham, NC 27707, USA.
  • Chdid L; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Lamson DR; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Laudeman CP; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Tarpley M; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Elsayed N; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Smith GR; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Zheng W; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
  • Dixon MS; Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA.
  • Williams KP; Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707, USA.
Molecules ; 29(13)2024 Jun 28.
Article en En | MEDLINE | ID: mdl-38999049
ABSTRACT
Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Piridinas / Pirimidinas / Proteínas Hedgehog / Simulación del Acoplamiento Molecular / Proteína con Dedos de Zinc GLI1 Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Piridinas / Pirimidinas / Proteínas Hedgehog / Simulación del Acoplamiento Molecular / Proteína con Dedos de Zinc GLI1 Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article