Triazolo[4,5-d]pyrimidin-5-amines based ERK3 inhibitors fail to demonstrate selective effects on adipocyte function
Andrei Belykh1, Izabela Hawro1, Katarzyna Kolczyńska-Matysiak1
1Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
Archives of Biochemistry and Biophysics
|November 22, 2023
Summary
Extracellular signal-regulated kinase 3 (ERK3) regulates lipolysis, but tested inhibitors showed non-selective effects. These compounds impact metabolic health by affecting multiple targets beyond ERK3.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Extracellular signal-regulated kinase 3 (ERK3), also known as MAPK6, is a kinase involved in numerous physiological and pathological processes.
- Targeting ERK3 offers potential therapeutic strategies for cancer, metabolic disorders like obesity and diabetes, and other somatic pathologies.
- ERK3 is a known regulator of lipolysis in adipocytes, making it a key target for metabolic research.
Purpose of the Study:
- To synthesize and evaluate triazolo[4,5-d]pyrimidin-5-amines as potential ERK3 inhibitors.
- To assess the selectivity and biological impact of these compounds on cellular metabolic state, specifically lipolysis.
- To investigate the direct and indirect effects of ERK3 inhibition on lipolytic enzymes and related proteins.
Main Methods:
- Synthesis of three triazolo[4,5-d]pyrimidin-5-amines.
- Utilized various adipocyte models to study lipolysis.
- Employed machine learning-based prediction to identify potential off-targets of the synthesized compounds.
Main Results:
- The synthesized compounds modulate lipolysis, but their effects are not solely dependent on ERK3 inhibition.
- ERK3 was found to regulate not only ATGL but also hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL).
- ERK3 also influences the abundance of fatty acid synthase (FASN) and protein kinase cAMP-activated catalytic subunit alpha (PKACα).
- Machine learning predictions revealed a broad range of potential targets for the tested compounds, indicating non-selectivity.
Conclusions:
- While the tested compounds inhibit ERK3 in vitro, their biological effects are complex and influenced by off-target interactions.
- The non-selective binding of these inhibitors to multiple targets modifies the biological outcome of ERK3 inhibition.
- Further research is needed to develop selective ERK3 inhibitors for therapeutic applications in metabolic diseases and cancer.
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