Validation of the Vps34 PI 3-kinase as a new potential drug target in insulin sensitization
Lead Research Organisation:
University College London
Department Name: Oncology
Abstract
This proposal aims to test the hypothesis that the Vps34 enzyme plays a role in metabolism. In our previous studies, using genetic approaches in the mouse and funded by the BBSRC, we have discovered that partial inactivation of Vps34 leads to improved glucose-tolerance and protection against the negative effects of a high fat diet. This suggests that Vps34 inhibitors could be useful in diseases such as diabetes. We now propose to test whether newly developed chemical blockers of Vps34 can induce the same effects as genetic inactivation of Vps34, in cell- and mouse-based models. This is a proof-of-concept project which, if the outcome is positive, can lay the foundations for Vps34 drug development and a translational programme of work.
Publications
Alliouachene S
(2016)
Inactivation of class II PI3K-C2a induces leptin resistance, age-dependent insulin resistance and obesity in male mice.
in Diabetologia
Bilanges B
(2019)
PI3K isoforms in cell signalling and vesicle trafficking.
in Nature reviews. Molecular cell biology
Bilanges B
(2017)
Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism.
in Nature communications
Conduit S
(2020)
Phosphoinositide lipids in primary cilia biology
in Biochemical Journal
Grieco G
(2020)
Class III PI3K Vps34 Controls Thyroid Hormone Production by Regulating Thyroglobulin Iodination, Lysosomal Proteolysis, and Tissue Homeostasis.
in Thyroid : official journal of the American Thyroid Association
Madsen RR
(2020)
Cracking the context-specific PI3K signaling code.
in Science signaling
Madsen RR
(2020)
PI3K in stemness regulation: from development to cancer.
in Biochemical Society transactions
Valet C
(2017)
A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth.
in Blood
Vanhaesebroeck B
(2021)
PI3K inhibitors are finally coming of age.
in Nature reviews. Drug discovery
| Description | We have discovered that inactivation of a PI 3-kinase enzyme (Vps34) at the organismal level leads to insulin sensitization and increased glucose tolerance. Using this award, we have shown that this occurs both upon genetic as well as pharmacological inactivation of this kinase. Our study thus identifies Vps34 as a new drug target for the treatment of insulin resistance in Type 2 diabetes, conditions in which the unmet therapeutic need remains substantial. |
| Exploitation Route | Pharma might consider developing/using vps34 PI 3-kinase inhibitors as insulin sensitizers. |
| Sectors | Healthcare |
| Description | Several companies have developed inhibitors against this isoform for PI 3-kinase, but have focused on oncology, rather than on metabolic sensitization as would be indicated by our key publication from this award. |
| First Year Of Impact | 2019 |
| Sector | Healthcare |
| Impact Types | Economic |
| Description | Deciphering PI3K biology in health and disease |
| Amount | € 495,745 (EUR) |
| Funding ID | Phd |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 11/2015 |
| End | 10/2019 |
| Title | vps34 mutant mice |
| Description | Mice in which the vps34 PI 3-kinase is inactivated in a constitutive or conditional manner. This mouse line can be used in pre-clinical models of disease, such as cancer and diabetes. We may ultimately licence these mice to pharma, as we have done for our other PI3K mutant mice. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2011 |
| Provided To Others? | Yes |
| Impact | - Extensive collaborations in UK, US and France. - Allowed other people to apply for grants using these materials - successful bid to BBSRC for programme grant follow-up funding |
| Description | Collaboration with Novartis Research Institution - Boston USA |
| Organisation | Novartis Institutes for BioMedical Research (NIBR) |
| Country | United States |
| Sector | Private |
| PI Contribution | We have received a small molecule inhibitor from Novartis under MTA, and tested this compound to validate our genetic data |
| Collaborator Contribution | Novartis provided a small molecule inhibitor against the vps34 Pi 3-kinase under MTA, |
| Impact | A manuscript describing the results of these studies has now been published (Bilanges et al - Nature Communications 2017) |
| Start Year | 2016 |