An integrated target validation and drug discovery platform for the identification of novel agents targeting genome stability for the treatment of cancer (360G-Wellcome-110578_A_15_Z)

Our goal is to translate our deep knowledge of the DNA Damage Response (DDR) into a portfolio of first-in-class DDR pathway-targeted small molecule cancer drugs that exploit the inherent genomic instability underlying the growth, progression and acquired treatment-resistance of cancer.Mutation and disruption of DDR systems is positively selected in most, if not all, tumours and is integral to the development of resistance to existing therapeutics. This new class of pathway-directed inhibitor drugs will be highly effective against specific tumour genetic backgrounds demonstrating low side effects and high tolerability appropriate for combination use with a range of current therapies.This proposal exploits the recently-elucidated and tumour-specific involvement of individual DDR pathways in genome instability and combines it with world-class expertise in structural biology, drug discovery and human tumour xenograft models along with AstraZeneca lead-finding support.The funding will support early optimisation for 3 projects that have established assays, chemical matter and crystallography together with hit finding for 2 additional targets. Our projected deliverables after 4 years are:1. two projects positioned to attract external onward funding with novel and developable lead matter, established SAR, tumour cell biology, in vivo (xenograft) proof of concept, filed patent application and a clear route to the clinic.2. one additional project with optimised lead matter ready for early discovery onward funding.