Identification and characterisation of new class of PI3K modulators in oncology

Projektinformationen

PI3K MODULATORS

ID Finanzhilfevereinbarung: 839032

DOI

10.3030/839032

Projekt abgeschlossen

EK-Unterschriftsdatum 10 April 2019

Startdatum 1 Mai 2019

Enddatum 30 April 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 212 933,76

EU-Beitrag

€ 212 933,76

Koordiniert durch

UNIVERSITY COLLEGE LONDON
United Kingdom

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

Berichtszeitraum: 2019-05-01 bis 2021-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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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