Targeting VPS34 in autophagy: An update on pharmacological small-molecule compounds

by Selleckchem | Aug 04 2023

VPS34 is well-known to be the unique member of the class III phosphoinositide 3-kinase (PI3K) family, forming VPS34 complex 1 and complex 2, which are involved in several key physiological processes. Of note, VPS34 complex 1 is an important node of autophagosome generation, which controls T cell metabolism and maintains cellular homeostasis through the autophagic pathway. And, VPS34 complex 2 is involved in endocytosis as well as vesicular transport, and is closely related to neurotransmission, antigen presentation and brain development. Due to the two important biological functions of VPS34, its dysregulation can lead to the development of cardiovascular disease, cancer, neurological disorders, and many types of human diseases by altering normal human physiology. Thus, in this review, we not only summarize the molecular structure and function of VPS34, but demonstrate the relationships between VPS34 and human diseases. Moreover, we further discuss the current small molecule inhibitors targeting VPS34 based upon the structure and function of VPS34, which may provide an insight into the future targeted drug development.

Comments:

VPS34, a member of the class III phosphoinositide 3-kinase (PI3K) family, plays a crucial role in various physiological processes. It forms two distinct complexes, VPS34 complex 1 and complex 2, each with unique functions and implications for human health. In this review, we will delve into the molecular structure and function of VPS34, explore its involvement in different biological processes, and highlight its associations with various human diseases. Additionally, we will discuss current research on small molecule inhibitors targeting VPS34, which hold promise as potential therapeutic agents in the future.

VPS34 complex 1 is primarily responsible for regulating autophagosome generation, a process essential for maintaining cellular homeostasis and controlling T cell metabolism. Autophagy, the degradation and recycling of cellular components, is crucial for cellular survival and adaptation under stress conditions. Dysregulation of VPS34 complex 1 can disrupt the autophagic pathway, leading to the development of cardiovascular disease, cancer, neurological disorders, and other human diseases. Understanding the molecular mechanisms underlying VPS34 complex 1 function and its involvement in disease pathology can provide valuable insights for targeted therapeutic strategies.

On the other hand, VPS34 complex 2 participates in endocytosis and vesicular transport, which are fundamental processes in intracellular trafficking and signal transduction. This complex is closely associated with neurotransmission, antigen presentation, and brain development. Any abnormalities in VPS34 complex 2 can contribute to neurological disorders and impact overall brain function. Elucidating the intricate relationship between VPS34 complex 2 and these physiological processes can aid in the development of therapeutic interventions for various neurological conditions.

Moreover, the review highlights the importance of investigating small molecule inhibitors targeting VPS34. By understanding the structural and functional aspects of VPS34, researchers have identified potential compounds that can selectively modulate its activity. These inhibitors hold promise as targeted drugs for the treatment of diseases associated with dysregulated VPS34 function. Further research and development in this area can pave the way for novel therapeutic approaches and contribute to the advancement of precision medicine.

In summary, this review provides a comprehensive overview of VPS34, emphasizing its role in autophagy, cellular homeostasis, endocytosis, and vesicular transport. The dysregulation of VPS34 can have profound implications for human health, leading to various diseases. The exploration of small molecule inhibitors targeting VPS34 presents an exciting avenue for future drug development and personalized treatment strategies.