Discovery of an activator of PI3Kα that can protect cells from dying in the case of injury and accelerate the regeneration of neurons
Any mechanic knows that it is far easier to stop a machine from working than it is to fix the machine and make it work better. Much of the effort that goes into drug development is aimed at discovering inhibitors to stop molecular machines that govern disease progression. Research into activators that can fix disease-linked molecular machines is underexplored.
The lipid kinase protein phosphoinositide 3-kinase alpha (PI3Kα) is a key molecular machine controlling the activities of our cells. It has an important role in mediating cell growth and survival, and it is frequently upregulated in cancer, so reducing its activity has been a major effort in drug discovery. However, because PI3Ks also play beneficial roles in wound healing, survival, and protection from stress, Roger Williams’ group in the LMB’s PNAC Division, together with Bart Vanhaesebroeck and Richard Angell’s groups at University College London, and researchers at AstraZeneca, have taken a different direction. They have been focussing on discovering activators to make this molecular machine work better.
The team, led by Bart Vanhaesebroeck at the UCL Cancer Institute, have discovered the first selective small molecule activator of PI3Kα, a compound that they call 1938. Using animal models, they demonstrated that short-term administration of 1938 can achieve therapeutic benefits in protecting hearts from dying after injury and increasing the ability of neurons to regenerate.
Grace Gong in Roger Williams’ group, Dom Bellini from the X-ray facility and Stephen McLaughlin from the LMB Biophysics Facility, used structural biology methods such as X-ray crystallography to show that 1938 activates PI3Kα by causing changes in the shape of the protein that enable it to work faster and produce more of the molecules that turn up the cell’s ability to resist and repair damage. Bart Vanhaesebroeck and Richard Angell groups used a combination of in vitro, cell, and animal models to understand how 1938 activates PI3Ka, what this activation leads to downstream in cells, and what are the therapeutic benefits.
They explored two potential therapeutic applications for 1938 that are in great clinical need, with no currently available clinical treatment. The first one focused on protecting the heart against ischemia reperfusion injury. During a heart attack or stroke, blood flow to cardiac and nerve tissue becomes restricted, starving cells of oxygen and potentially killing them if not restored. Re-perfusion methods, such as inserting a stent into vessels, are the first line of therapy, but paradoxically the flood of oxygen back into the tissue can damage tissue in the process of saving it. A team led by Sean Davidson and Derek Yellon showed that administering the 1938 compound during the first 15 min of reperfusion of the infarcted heart provided substantial tissue protection. This was shown by increased tissue survival and reduced infarct size – the area of dead tissue or necrosis caused by inadequate blood supply.
James Philips’ group then explored the potential of 1938 as a regenerative medicine. They added the compound to rat spinal nerve cells in culture, and found that it significantly increased neurite outgrowth, which is a process where developing neurons throw out new projections as they grow in response to stimulus and cues. Finally, they tested a rat model of sciatic nerve injury, delivering the 1938 compound into the injured nerve. They found that 1938 treatment resulted in an impressive rate of recovery, as shown by increased activity of a muscle in the hind leg.
The research provides an example of how directly activating PI3Kα offers great potential and creates a paradigm shift from looking only for kinase inhibitors to also developing kinase activators for therapeutic benefit.
This work was funded by UKRI MRC, NIHR UCLH Biomedical Research Centre, the LMB’s and AstraZeneca’s Blue Sky Collaboration (a research collaboration between AstraZeneca UK Limited and the Medical Research Council, reference BSF33), the Rosetrees Trust, Cancer Research UK, BBSRC, the British Heart Foundation, Fidelity Foundation, UCL Enterprise HEIF Knowledge Exchange and Innovation Fund and Wellcome Trust.
In addition, this project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 839032.
A small molecule PI3Kα activator for cardioprotection and neuroregeneration. Gong, G.Q., Bilanges, B., Allsop, B., Masson, G.R., Roberton, V., Askwith, T., Oxenford, S., Madsen, R.R., Conduit, S.E., Bellini, D., Fitzek, M., Collier, M., Najam, O., He, Z., Wahab, B., McLaughlin, S.H., AW Edith Chan, Feierberg, I., Madin, A., Morelli, D., Bhamra, A., Vinciauskaite, V., Anderson, K.E., Surinova, S., Pinotsis, N., Lopez-Guadamillas, E., Wilcox, M., Hooper, A., Patel, C., Whitehead, M.A., Bunney, T.D, Stephens, L.R., Hawkins, P.T., Katan, M., Yellon, D.M., Sean M Davidson, Smith, D.M. Phillips, J.B., Angell, R., Williams, R.L., & Vanhaesebroeck, B. Nature
Roger Williams group page
Bart Vanhaesebroeck group page
Richard Angell page
Sean Davidson page
Derek Yellon page
James Philips page