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Published on: January 7, 2019
Development and biological evaluation of potent and selective c-KIT(D816V) inhibitors
Soyoung Lee1, Hyunseung Lee, Jinhee Kim
1Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Yuseong-gu, E6-4, Daejeon 305-701, Korea.
Abstract:
The c-KIT tyrosine kinase has emerged as a potential therapeutic target for an array of diseases. However, there exists a drug resistance that is caused by mutations in c-KIT; therefore, c-KIT remains as a clinical challenge due to limited effective treatment options for therapies. For example, the acquired activating point mutation D816V significantly impairs the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular level will aid in designing and developing particular inhibitors with the potential to overcome these resistance mutations. We undertake a structure-based de novo design of 7-azaindole as the molecular core using the modified scoring function. This approach led to an identification of new c-KIT inhibitors over 100-fold specific for the D816V mutant relative to the wild-type c-KIT with nanomolar inhibitory activity. More importantly, these compounds potently inhibit clinically relevant D816V mutations of c-KIT in biochemical and cellular studies.
Insights
New 7-azaindole inhibitors show over 100-fold specificity for the drug-resistant KIT D816V mutation. These compounds offer potential new therapies for diseases driven by resistant KIT mutations.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- The c-KIT tyrosine kinase is a therapeutic target for various diseases.
- Drug resistance, particularly the KIT D816V mutation, limits the efficacy of current targeted therapies.
- Understanding resistance mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To design novel c-KIT inhibitors that overcome drug resistance mutations.
- To identify specific inhibitors targeting the KIT D816V mutant.
Main Methods:
- Structure-based de novo design utilizing a 7-azaindole core.
- Modified scoring function for inhibitor design.
- Biochemical and cellular assays to evaluate inhibitor activity and specificity.
Main Results:
- Identification of new c-KIT inhibitors with over 100-fold specificity for the D816V mutant compared to wild-type c-KIT.
- Achieved nanomolar inhibitory activity against the D816V mutant.
- Demonstrated potent inhibition of clinically relevant KIT D816V mutations in biochemical and cellular studies.
Conclusions:
- The developed 7-azaindole-based inhibitors are highly specific for the KIT D816V resistance mutation.
- These novel compounds represent promising therapeutic candidates for overcoming c-KIT-mediated drug resistance.
- Structure-based design is effective for developing targeted therapies against resistant kinase mutations.
