Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Oncology

Background:

• Tumor-acquired resistance to tyrosine kinase receptor (TKR) inhibitors is a significant challenge in cancer therapy.
• Mutations in the c-Kit receptor tyrosine kinase (TKR) are implicated in gastro-intestinal stromal tumors (GIST), leukemia, and mastocytosis, often limiting the effectiveness of current inhibitors.
• Developing novel inhibitors capable of targeting mutated c-Kit is crucial for overcoming treatment resistance.

Purpose of the Study:

• To propose and validate a new in silico protocol for identifying novel c-Kit inhibitors.
• To design compounds that can effectively bind to mutated c-Kit proteins, including those conferring resistance.
• To explore potential therapeutic strategies against c-Kit-driven malignancies resistant to existing treatments.

Main Methods:

• A combined ligand-based and structure-based in silico approach was employed.
• The DRUDIT web server was utilized for the ligand-based method.
• Induced Fit Docking (IFD) studies were performed for structure-based analysis.

Main Results:

• The protocol successfully identified potential new c-Kit inhibitors targeting V654A and T670I mutated proteins.
• In silico analysis suggests these inhibitors may overcome resistant mutations, such as D816H.
• The top-ranked compounds, 630705 and SML1348, demonstrated significant binding affinities to mutated c-Kit forms (T670I and V654A, respectively).

Conclusions:

• The proposed in silico protocol is effective in discovering novel c-Kit inhibitors against resistant mutations.
• The identified compounds show promise for overcoming tumor-acquired resistance in c-Kit-driven cancers.
• This approach offers a valuable strategy for developing next-generation TKR inhibitors.