Identification and characterisation of new class of PI3K modulators in oncology

Informazioni relative al progetto

PI3K MODULATORS

ID dell’accordo di sovvenzione: 839032

DOI

10.3030/839032

Progetto chiuso

Data della firma CE 10 Aprile 2019

Data di avvio 1 Maggio 2019

Data di completamento 30 Aprile 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 212 933,76

Contributo UE

€ 212 933,76

Coordinato da

UNIVERSITY COLLEGE LONDON
United Kingdom

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

Periodo di rendicontazione: 2019-05-01 al 2021-04-30

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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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