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H2020Individual fellowship2019–2021

PI3K MODULATORS · Identification and characterisation of new class of PI3K modulators in oncology

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2019-05-01 → 2021-04-30
EU contribution
€212,934
Participants
1
Scheme
MSCA-IF-EF-ST

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Results in brief

Identification and characterisation of new class of PI3K modulators in oncology

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.

Data: CORDIS, © European Union

Project objective

PI3K signalling is a critical regulator of many cellular functions including cell growth and survival, and is deregulated in cancer and auto-immunity.This proposal is based on the concept to cause cell death by hyperactivating signalling in cancer cells above a tolerable threshold. This idea has been previously proposed for other kinases, but no small-molecule activators were available to formally test the idea. This proposal focuses on activators of the leukocyte-enriched PI3Kd, an isoform of PI3K that is involved in immune regulation and haematological malignancies.The 3 key objectives and their approaches are:1. To discover and characterise small-molecule PI3Kd activators. This will be achieved using a combination of virtual screening and high throughput screening.2. To understand the mechanism of PI3Kd activation. This enables understanding of how these activators function, and provides structural data that can be used for structure-based design and compound improvement. This will be achieved using structural biology (HDX-MS and crystallography), biochemical (lipid kinase) and biophysical (binding) assays.3. To determine the activity of PI3Kd activators in haematopoietic malignancies. In order to use PI3Kd activators in cancer therapy, it is critical to determine the conditions under which hyperactivation of PI3Kd results in cancer cell death. This will be achieved with a panel of B and T-cell lymphoma cell lines using cell viability assays under different conditions.These objectives integrate my expertise in compound screening, molecular modelling and compound design with the world-leading expertise of the Host Lab in PI3K signalling, cancer biology and drug development. This proposal aims to make breakthroughs in understanding PI3K signalling, its exploitation in drug development and in cancer-therapy. This will be a key turning point in my scientific career and facilitate PI3K drug development collaborations of the Host Lab with the pharmaceutica.

Original text from CORDIS.

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Data: CORDIS, © European Union