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Screening methods for AMP-activated protein kinase modulators: a patent review
Joungmok Kim1, Joonsoo Shin, Joohun Ha
1Kyung Hee University, School of Dentistry, Oral Biochemistry and Molecular Biology , Seoul , Republic of Korea.
Introduction:
AMP-activated protein kinase (AMPK) functions as a cellular energy gauge that maintains cellular homeostasis and has been suggested to play important roles in tumorigenesis, lifespan and autophagy. Accordingly, AMPK is a potential target of drugs for controlling a growing number of human diseases ranging from metabolic disorders to cancer, highlighting the need for rational and robust screening systems for identifying compounds that modulate AMPK.
Areas Covered:
The relevant screening methods in the patent and scientific literature were analyzed, and key features of direct AMPK modulators are discussed in the context of their physiological relevance and the three-dimensional structure of the AMPK complex.
Expert Opinion:
The mechanism of action of modulators is important in designing drugs with enhanced efficacy, specificity and stability. Most patented assay formats for identifying AMPK modulators are based on classical enzyme assays that monitor AMPK activity or changes in AMPK-dependent cellular physiology. However, these systems do not provide information about underlying mechanisms. Two patented assay systems use a specific domain or the three-dimensional structure of AMPK to identify AMPK modulators. The recent identification of two AMPK modulators, A-769662 and C-2 (or its prodrug, C-13), suggests the promise of structure-based assays in discovering more potent and specific modulators of AMPK.
Insights
AMP-activated protein kinase (AMPK) is crucial for cellular energy balance and disease treatment. Structure-based assays show promise for discovering potent and specific AMPK modulators, advancing drug development for various conditions.
Area of Science:
- Biochemistry and Molecular Biology
- Drug Discovery and Development
- Cellular Metabolism
Background:
- AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, regulating homeostasis.
- AMPK plays significant roles in tumorigenesis, lifespan, and autophagy.
- AMPK is a key therapeutic target for metabolic disorders and cancer.
Purpose of the Study:
- To analyze and discuss screening methods for identifying compounds that modulate AMPK activity.
- To highlight the importance of understanding modulator mechanisms for drug design.
- To evaluate the potential of structure-based assays for discovering novel AMPK modulators.
Main Methods:
- Comprehensive analysis of screening methods described in patent and scientific literature.
- Discussion of direct AMPK modulator features, physiological relevance, and structural context.
- Evaluation of classical enzyme assays versus structure-based assay systems.
Main Results:
- Classical enzyme assays and cell-based physiological assays lack mechanistic insights.
- Patented assays utilizing specific AMPK domains or its 3D structure are emerging.
- Identification of A-769662 and C-2/C-13 demonstrates the efficacy of structure-based approaches.
Conclusions:
- Understanding modulator mechanisms is vital for developing drugs with improved efficacy, specificity, and stability.
- Structure-based assays offer a promising avenue for discovering potent and specific AMPK modulators.
- Advancements in screening systems are crucial for targeting AMPK in various human diseases.
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