Establishing a novel first-in-class PI3K/PDGFR/Wnt pathway inhibitor for treatment of glioblastoma

Abstract

Glioblastoma (GBM) is the most common and deadly brain cancer of the central nervous system. GBM exhibits a dismal prognosis of 5% patients surviving beyond 5 years of initial diagnosis, hence it is a major unmet need. The high plasticity of glioma cancer stem cell population contributes to an extreme form of therapyresistant tumour and poses a major challenge to monotherapeutic drugs. Hence, a successful therapeutic strategy for GBM will require pleiotropic interventions targeting diverse survival pathways of the disease.

To achieve this, I have collaborated with medicinal chemists at the University of Arizona to develop a novel first-in-class PI3K, PDGFR, and Wnt pathway inhibitor. This inhibitor was developed using structural-activity-relationship analysis on the initial compound, DYR533 which is on the critical path for clinical trials in Alzheimer’s disease patients. A primary aim of this thesis is to identify a compound that exhibits polypharmacology against PDGFR, PI3K, and Wnt signalling, which are the major oncogenic signalling pathways in glioblastoma. To identify this molecule, as part of the first aim of my thesis I screened over 200 compounds to identify the lead compound, DYR726, which potently inhibits PI3K and PDGFRα while simultaneously ablating Wnt signalling in primary patient derived glioma cells. As part of my second and third aims, results show that DYR726 is significantly superior at reducing cell viability of glioblastoma primary patient derived cells compared to multiple FDA approved clinical kinase inhibitors. DYR726’s ability to specifically target distinct classes of kinases was a result of designed and controlled de novo synthesis. Hence the molecule has excellent kinase specificity with less off-targets compared to vast majority of FDA approved kinase inhibitors. This is corroborated by a therapeutic window seen in non cancerous cells and reduced toxicity in mice. While testing the last two aims of my project, I found that DYR726 has excellent kinetic solubility, in vivo blood-brain barrier penetrance, and good in vivo half-life. DYR726 significantly reduced tumour burden in an in vivo triple-negative breast cancer mouse syngraft model, along with significantly increasing overall survival in an in vivo glioblastoma mouse allograft model. Furthermore, treating glioblastoma cells with DYR726 and temozolomide or radiotherapy both have additive effects of inducing cytotoxicity. This proves the clinical relevancy of DYR726 as not only a monotherapeutic option, but as a combination therapy with the preexisting treatments for glioblastoma patients. And due to their novelty, DYR726 and its derivatives have been filed for a patent, PCT/US2023/025972. Together, these experiments show that DYR726 is a novel pleiotropic kinase inhibitor with the potential to significantly improve the lives of brain tumour patients.

Date of Award	2024
Original language	English
Awarding Institution	University of Dundee
Supervisor	Sourav Banerjee (Supervisor), Laureano de la Vega (Supervisor) & Albena Dinkova-Kostova (Supervisor)