Identification and characterisation of new class of PI3K modulators in oncology

Project Information

PI3K MODULATORS

Grant agreement ID: 839032

DOI

10.3030/839032

Project closed

EC signature date 10 April 2019

Start date 1 May 2019

End date 30 April 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

UNIVERSITY COLLEGE LONDON
United Kingdom

Periodic Reporting for period 1 - PI3K MODULATORS (Identification and characterisation of new class of PI3K modulators in oncology)

Reporting period: 2019-05-01 to 2021-04-30

Summary of the context and overall objectives of the project

The phosphoinositide 3-kinase (PI3K) lipid kinases play a critical role in the regulation of many cellular functions including cell proliferation, survival and migration. The class IA PI3Ks are heterodimers of a p110 catalytic subunit (alpha, beta, delta) and a p85 regulatory subunit. Whereas PI3Kalpha and PI3Kbeta are ubiquitously expressed, PI3Kdelta is highly-enriched in leukocytes. Class IA PI3Ks mainly signal downstream of tyrosine kinases, and phosphorylate the PI(4,5)P2 lipid to generate PI(3,4,5)P3. PIP3 activates a range of signalling proteins including the Akt protein kinase. Given the role of PI3K in cell growth and proliferation, it has been a major target in drug discovery for the past few decades. The overall objectives of this project include to characterise novel allosteric modulators of PI3K using structural, biochemical and cellular approaches.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In this project, we discovered and characterised an allosteric modulator of PI3K, and using a combination of structural biology techniques (HDX-MS, crystallography, molecular modelling), enzyme biology (lipid kinase assays, membrane binding assays) and cellular approaches, we discovered a unique mechanism of action for our modulator, and explored different therapeutic potential applications. The work resulted in a manuscript (to be submitted) and a patent application. There is also the potential for commercial exploitation of the results.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We expect findings of this project to open new fields of research in PI3K drug discovery, and kinase drug discovery in general. Our results demonstrate that although PI3K is widely implicated in cancer and has been a major target in anticancer drug discovery, there is also great potential for PI3K as a therapeutic target in other diseases and applications.

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