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Published on: February 9, 2021
Synthesis and pharmacological evaluation of thieno[2,3-b]pyridine derivatives as novel c-Src inhibitors
Isabelle Pevet1, Cédric Brulé, André Tizot
1Institut de Recherches Servier, Suresnes, France.
Abstract:
Among the recently investigated targets for cancer therapy is the c-Src non-receptor tyrosine kinase. Indeed research around deregulated activity of this enzyme has proven its role in tumor progression, while the beneficial effects of c-Src inhibitors in several pathological models has also been demonstrated. We report here the preparation and pharmacological profile of a novel series of c-Src inhibitors that was elaborated around a 3-amino-thieno[2,3-b]pyridine discovered during an HTS campaign. c-Src enzyme inhibition and c-Src inhibition were investigated in a series of related compounds derived from the initial hit. Molecular modeling as well as X-ray studies on one active compound allowed us to hypothesize on ligand orientation and interactions within the ATP hydrophobic pocket. Design and synthesis of structural analogs then led to new ligands possessing quite efficient enzymatic and c-Src inhibition. The structure-activity elements disclosed in this study shed light on the role played by substituents on the thienopyridine ring as well as the impact of other aromatic moieties in the molecule when interacting with the enzyme.
Insights
Researchers developed novel c-Src inhibitors based on a thienopyridine scaffold. These compounds show promising efficacy in inhibiting c-Src kinase activity, offering potential for cancer therapy development.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Deregulation of c-Src tyrosine kinase is implicated in cancer progression.
- c-Src inhibitors have demonstrated therapeutic benefits in preclinical cancer models.
Purpose of the Study:
- To design, synthesize, and characterize a novel series of c-Src inhibitors.
- To investigate the structure-activity relationships of these inhibitors for optimized efficacy.
Main Methods:
- High-throughput screening (HTS) identified an initial hit compound.
- Medicinal chemistry efforts involved structural modifications and synthesis of analogs.
- Enzyme inhibition assays and cellular assays were used to evaluate compound activity.
- Molecular modeling and X-ray crystallography provided insights into ligand-enzyme interactions.
Main Results:
- A novel series of 3-amino-thieno[2,3-b]pyridine derivatives were synthesized.
- Several analogs exhibited potent inhibition of c-Src kinase activity.
- Structure-activity relationship studies elucidated key interactions within the ATP-binding pocket.
Conclusions:
- The developed thienopyridine-based compounds are effective c-Src inhibitors.
- These findings provide a foundation for developing new targeted cancer therapies.
- Understanding ligand interactions is crucial for optimizing inhibitor design.
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