Design and synthesis of PIP analogues as inhibitors of AKT localisation in PTEN-deficient tumours

Genetic alterations leading to dysregulation of the PI3K/AKT pathway are one of the most common genetic drivers across a wide range of tumour types. These changes generally consist of activating mutations in the gene coding for

phosphatidylinositol 3 kinase alpha (PI3Ka), or deletion/deactivation of the phosphatase PTEN. The result of either change is a loss of control of the PIP2-PIP3 system, leading to accumulation of PIP3 and subsequent hyper-activation of the AKT pathway.

Drugs targeting the PI3K/AKT pathway have proven to be useful in treatment of some patients, but are limited by toxicity due to the ubiquitous role of PI3K/AKT signalling, as well as resistance mediated by PTEN loss of function. We are working on a series of truncated PIP analogues that remain under the control of PI3Ka/PTEN but with reduced membrane affinity due to alterations in the lipid side chain.

It is expected that these compounds will accumulate in the PIP3 form in PTEN deficient cells, leading to deactivation of AKT, but be in a less activated state in healthy cells. This approach would therefore directly target both the toxicity and resistance issues seen with conventional PI3K/AKT pathway inhibitors.

Aims of this project:

1) Structure-based design and stereo-controlled synthesis of PIP analogues, targeting a small group of compounds with variable membrane localisation through modification of the side chain using the route shown.

2) Biological evaluation of novel compounds prepared to evaluate their cytotoxicity and impact on AKT localisation and signalling pathways.

3) Deconvolute the mechanism of action of current and novel PIP analogues through phosphoproteome assays and development of chemical probes to identify cellular binding partners of active PIP analogues.