Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• c-Kit receptor tyrosine kinase is crucial for intracellular signaling and its mutations are linked to various cancers.
• Tyrosine kinase inhibitors targeting c-Kit show promise in cancer treatment but face emerging drug resistance.
• Development of novel inhibitors is needed to overcome resistance mutations, such as Val654.

Purpose of the Study:

• To identify novel natural-based compounds with potent inhibitory activity against c-Kit.
• To assess the efficacy of identified compounds against common resistance mutations.
• To enhance the binding affinity and metabolic stability of lead compounds using fragment-based drug design.

Main Methods:

• Virtual screening of a natural-based compound library against c-Kit.
• In vitro inhibitory activity assays and single point mutation docking studies.
• Fragment-based drug design to optimize lead compound properties.

Main Results:

• Three natural compounds (2, 5, and 6) exhibited nanomolar inhibitory activity against c-Kit.
• These compounds remained effective against the Val654 resistance mutation found in imatinib-resistant cells.
• A novel derivative (F1) derived from fragment-based design showed enhanced binding affinity, stability, and binding free energy compared to the parent compound.

Conclusions:

• Natural-based compounds can serve as a basis for developing potent c-Kit inhibitors.
• The identified compounds and their derivatives demonstrate potential for overcoming resistance to existing therapies.
• Fragment-based drug design is an effective strategy for improving the pharmacological properties of anti-cancer drug candidates.