Identification and characterisation of new class of PI3K modulators in oncology

Información del proyecto

PI3K MODULATORS

Identificador del acuerdo de subvención: 839032

DOI

10.3030/839032

Proyecto cerrado

Fecha de la firma de la CE 10 Abril 2019

Fecha de inicio 1 Mayo 2019

Fecha de finalización 30 Abril 2021

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 212 933,76

Aportación de la UE

€ 212 933,76

Coordinado por

UNIVERSITY COLLEGE LONDON
United Kingdom

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

Período documentado: 2019-05-01 hasta 2021-04-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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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