A Small-Molecule PI3Kα Activator Demonstrates Therapeutic Potential for Cardioprotection and Neuroregeneration

In a new study, researchers from University College London (UCL), the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, and AstraZeneca identified a new compound that can stimulate nerve regeneration after injury and protect heart tissue from damage following a heart attack. The relevant findings were published online in the journal Nature on May 24, 2023, with the paper titled “A small-molecule PI3Kα activator for cardioprotection and neuroregeneration”.

Specifically, these authors identified a small molecule compound named "1938," which activates the PI3K (Phosphoinositide 3-kinase) signaling pathway and is involved in cell growth. The results of this preliminary study showed that the compound increased neuronal growth. Moreover, in animal models, it reduced cardiac tissue damage after major trauma and promoted the regeneration of lost motor function in a nerve injury model. Although further research is needed to translate these findings into clinical applications, 1938 is one of the few compounds under development that promote nerve regeneration, and currently, there are no approved drugs for promoting nerve regeneration on the market.

PI3K is a kinase that helps control cell growth. It is active in a variety of situations, such as initiating wound healing, but its function can also be hijacked by cancer cells, allowing them to proliferate. Therefore, anticancer drugs that inhibit PI3K have been developed to limit tumor growth. However, the clinical potential of activating the PI3K signaling pathway remains largely untapped.

"Kinases are key molecular machines that control the activity of our cells, and they are the targets of many drugs," said Dr. Roger Williams of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. "Our goal is to find an activator for one of these molecular machines with the aim of making this molecular machine work better. We have discovered that we can directly activate a kinase with a small molecule, achieving therapeutic effects that protect the heart from damage and stimulate nerve regeneration in animal studies."

In this new study, the authors screened thousands of molecules from a compound library to obtain a molecule that could activate the PI3K signaling pathway. They found that a compound named 1938 could reliably activate PI3K and evaluated its biological effects through experiments on cardiac tissue and nerve cells.

These authors found that administering 193 within the first 15 minutes of blood flow restoration after a heart attack provided substantial cardiac tissue protection in a preclinical model. Typically, when blood flow is restored, an area of dead tissue forms, which may lead to subsequent heart problems.

When 1938 was added to laboratory-cultured neurons, the growth of the neurons significantly increased. They also tested it on a rat model with sciatic nerve injuries, and delivering 1938 to the injured nerve led to increased recovery of the hind leg muscles, indicating nerve regeneration.

Regarding the biochemical experimental data from 1938, the image is from Nature, 2023, doi:10.1038/s41586-023-05972-2。

Professor James Phillips from the UCL School of Pharmacy said, "There are currently no drugs approved for nerve regeneration, and nerves can be damaged due to injury or disease, creating a significant unmet need. Our findings suggest that drugs activating PI3K have the potential to accelerate nerve regeneration, and crucially, localized drug delivery can avoid off-target effects that have been an issue with other failed compounds."

In view of these positive findings, these authors are now committed to developing new therapies for peripheral nerve injuries, such as those with severe hand and arm injuries. They are also exploring whether PI3K activators can be used to help treat damage to the central nervous system, such as spinal cord injuries, strokes, or neurodegenerative diseases.

"This is a typical example of interdisciplinary research, where professionals from basic science, drug development, and clinical research have united around an innovative idea, also bridging the gap between academia and industry," said Professor Bart Vanhaesebroeck of the UCL Cancer Institute, the corresponding author of the paper.BioValley Bioon.com）

References:

Grace Q. Gong et al. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature, 2023, doi:10.1038/s41586-023-05972-2.