Medicinal Chemistry Expertise

Pseudokinase/TRB3

Pseudokinase/TRB3

• Pseudokinases act as signal transducers by assembling components of signaling networks, or as allosteric activators/inhibitors of active protein kinases.
• Pseudokinases are proteins that possess many of the features of protein kinases but lack key residues, which were in the past were thought to be required for the ability to phosphorylate protein substrates.
• Some pseudokinases utilize non-canonical residues to perform as enzymes or have very low activity turnover rates, yet are involved in signaling and regulatory processes.
• Tribbles-3 (TRB3), a pseudokinase and negative regulator of AKT kinase, plays a critical role in sustaining and amplifying proinflammatory signals in metabolic tissues.
• Cytokines (IL-1β and TNF-α) as well as fatty acids are known to activate proinflammatory signaling via MLK3 and JNK.
• MLK3 activation induces and stabilizes TRB3.
• Additionally, MLK3-triggered JNK kinase can directly phosphorylate TRB3, increasing binding affinity and inhibition of AKT kinase.
• These results identify TRB3 as a potential drug target, inhibition of which could both diminish inflammation and maintain insulin sensitivity.
• In addition, TRB3 in genetic studies has been linked to neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease.
• Califia Bio is investigating the potential of TRB3 modulating compounds for the treatment of diabetes and neurodegenerative diseases.