News

Home page

Nature: PI3Kα small molecule activator for cardioprotection and neuroregeneration

Time：

2023-05-30

The PI3K family consists of three classes of isozymes, of which type IA (class IA PI3K) has been most extensively and intensively studied and consists of PI3K p110 catalytic subunits (PI3Kα, PI3Kβ and PI3Kδ) and PI3K p85 regulatory subunits with lipid kinase activity and protein kinase activity. type IA PI3K and its effectors AKT and mTORC1 are overactivated in cancer and the immune system, which has driven the widespread development of PI3K pathway inhibitors.

　　In addition, activation of the PI3K pathway may have therapeutic benefits in terms of tissue protection and regeneration. In models of cell and tissue injury, PI3K inhibitors inhibit the protective effects of growth factors and other drugs, thereby affecting protection against ischemia-reperfusion injury (IRI) (e.g., neurons after stroke, cardiomyocytes after myocardial infarction), protection against ionizing radiation, against tissue and wound repair, and against neuroprotection or regeneration.

　　Recently, researchers from University College London and AstraZeneca published a research paper in the journal Nature entitled: A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

　　The study reveals that a small-molecule activator of PI3Kα, UCL-TRO-1938 (referred to as 1938), can stimulate neuroregeneration after injury and protect heart tissue from damage during a heart attack.

800

Inhibitors targeting the PI3K pathway have been widely used to treat diseases with excessive PI3K activation, including cancer and immune dysregulation. Several studies have been conducted to activate the PI3K pathway through genetic and non-genetic strategies, the former including expression of genes encoding PI3Kα or AKT, or knockdown/knockdown of PTEN (a lipid phosphatase that downregulates PISK signaling), and the latter including p85-binding phosphopeptides, PTEN inhibitors, etc., but these have poor drug properties and the mechanism of PI3K pathway activation is unclear , with poor selectivity for target proteins.

　　Therefore, harnessing the benefits of kinase signaling through direct kinase activators remains an under-explored area of drug development.

　　In this latest study, researchers from University College London (UCL) and AstraZeneca collaborated to marshal thousands of molecules from a library of compounds to discover molecules that could activate the PI3K signaling pathway. They identified a small molecule compound called UCL-TRO-1938 (referred to as 1938) that acts as a small molecule activator of PI3Kα and evaluated its biological effects through experiments on heart tissue and nerve cells.

800

UCL-TRO-1938的结构

1938 mutagenically activates PI3Kα through a unique mechanism that enhances multiple steps of the PI3Kα catalytic cycle and causes local and global conformational changes in PI3Kα structure, and it has specific effects on PI3Kα. This study also found that treatment with 1938 within 15 minutes prior to ischemia-reperfusion following a heart attack provided substantial cardiac tissue protection in a mouse model and enhanced nerve regeneration following nerve injury after local administration. And neuronal growth was significantly enhanced when 1938 was added to laboratory cultured nerve cells.

800

　　Overall, the study identifies a small molecule compound that directly and specifically activates PI3Kα activity, which protects heart tissue and promotes nerve regeneration through short-term activation of PI3Kα, demonstrating the therapeutic potential of activating kinases, a new area of drug development that is currently unexplored.

　　The team said that the goal of the study was to find activators of kinases, a "molecular machine" that is key to regulating our cellular activities and a popular target for various drugs, so that they can work better. The study demonstrated in an animal model that it is possible to use small molecules to directly activate the kinase PI3Kα to protect the heart from damage and stimulate nerve regeneration.

　　There are currently no approved drugs that enable nerve regeneration, and there is a huge unmet need for nerves that may be damaged by injury or disease. The results of this study suggest that drugs that activate PI3K have the potential to accelerate nerve regeneration and, more importantly, that they can be administered locally, thus avoiding the off-target problems that have led to the failure of other compounds.

　　Link to the paper:https://www.nature.com/articles/s41586-023-05972-2