Discovery and characterization of novel FGFR1 inhibitors in triple-negative breast cancer via hybrid virtual screening and molecular dynamics simulations.
Bioorg Chem
; 150: 107553, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-38901279
ABSTRACT
The overexpression of FGFR1 is thought to significantly contribute to the progression of triple-negative breast cancer (TNBC), impacting aspects such as tumorigenesis, growth, metastasis, and drug resistance. Consequently, the pursuit of effective inhibitors for FGFR1 is a key area of research interest. In response to this need, our study developed a hybrid virtual screening method. Utilizing KarmaDock, an innovative algorithm that blends deep learning with molecular docking, alongside Schrödinger's Residue Scanning. This strategy led us to identify compound 6, which demonstrated promising FGFR1 inhibitory activity, evidenced by an IC50 value of approximately 0.24 nM in the HTRF bioassay. Further evaluation revealed that this compound also inhibits the FGFR1 V561M variant with an IC50 value around 1.24 nM. Our subsequent investigations demonstrate that Compound 6 robustly suppresses the migration and invasion capacities of TNBC cell lines, through the downregulation of p-FGFR1 and modulation of EMT markers, highlighting its promise as a potent anti-metastatic therapeutic agent. Additionally, our use of molecular dynamics simulations provided a deeper understanding of the compound's specific binding interactions with FGFR1.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ensayos de Selección de Medicamentos Antitumorales
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Inhibidores de Proteínas Quinasas
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Proliferación Celular
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Relación Dosis-Respuesta a Droga
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Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos
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Simulación de Dinámica Molecular
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Neoplasias de la Mama Triple Negativas
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2024
Tipo del documento:
Article
País de afiliación:
China