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Discovery of 4-aminoquinolines as highly selective TGFßR1 inhibitors with an attenuated MAP4K4 profile for potential applications in immuno-oncology.
Kharbanda, Anupreet; Tran, Phuc; Zhang, Lingtian; Leung, Yuet-Kin; Li, Hong-Yu; Frett, Brendan.
Afiliación
  • Kharbanda A; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Tran P; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Zhang L; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Leung YK; Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
  • Li HY; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: HLi2@uams.edu.
  • Frett B; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: BAFrett@uams.edu.
Eur J Med Chem ; 225: 113763, 2021 Dec 05.
Article en En | MEDLINE | ID: mdl-34419892
The tumor microenvironment contains high concentrations of TGFß, a crucial immunosuppressive cytokine. TGFß stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFßR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFßR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFßR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFßR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFßR1 inhibitor that has potential applications in immuno-oncology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Péptidos y Proteínas de Señalización Intracelular / Descubrimiento de Drogas / Receptor Tipo I de Factor de Crecimiento Transformador beta / Aminoquinolinas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Péptidos y Proteínas de Señalización Intracelular / Descubrimiento de Drogas / Receptor Tipo I de Factor de Crecimiento Transformador beta / Aminoquinolinas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Francia