Therapeutic targeting for ovarian cancer

High-grade serous carcinoma is the commonest type of ovarian cancer and accounts for
approximately two-thirds of all cases and nearly 80% of deaths. Treatment relies on the use of
platinum agents but resistance arises, this being associated with amplification of the CCNE1 gene.
The protein product of this gene (cyclin E1) is a cell cycle regulator that binds to and activates the
kinase cdk2 to promote proliferation. Thus, the cyclin E1/cdk2 protein/protein interaction (PPI)
offers an opportunity for an urgently required targeted therapy. This project will exploit the patented
covalent screening platform (qIT) established during previous ICB studentships to define novel
chemical entities to regulate this interaction. In addition to generating novel compounds targeting
this PPI, further physical sciences novelty will include (a) development of methods for random
introduction of a linker/acrylamide unit into a fragment to maximise library diversity from a fixed
number of fragments; (b) development of novel, tunable electrophilic warheads based on sulfur
amination chemistry developed by the Bull group; and (c) construction of an appropriately
functionalised fragment library incorporating novel stereodefined 3D-structures derived from the
combined expertise of the Armstrong and Bull groups on the efficient asymmetric synthesis of new
substituted small-ring heterocycles (e.g. oxetanes, azetidines) and spiro/bicyclic amines. This
important latter goal will allow exploration of new regions of 3D-chemical space, likely to enhance
the identification of compounds that can disrupt PPIs.

Addressing UK skills demand: The most important impact of the CDT will be to train a new generation of Chemical Biology PhD graduates (~80) to be future leaders of enterprise, molecular technology innovation and translation for academia and industry. They will be able to embrace the life science's industrialisation thereby filling a vital skills gap in UK industry. These students will be able to bridge the divide between academia/industry and development/application across the physical/mathematical sciences and life sciences, as well as the human-machine interfaces. The technology programme of the CDT will empower our students as serial inventors, not reliant on commercial solutions.
CDT Network-Communication & Engagement: The CDT will shape the landscape by bringing together >160 research groups with leading players from industry, government, tech accelerators, SMEs and CDT affiliates. The CDT is pioneering new collaboration models, from co-located prototyping warehouses through to hackathons-these will redefine industry-academic collaborations and drive technology transfer.
UK plc: The technologies generated by the CDT will produce IP with potential for direct commercial exploitation and will also provide valuable information for healthcare and industry. They will redefine the state of the art with respect to the ability to make, measure, model and manipulate molecular interactions in biological systems across multiple length scales. Coupled with industry 4.0 approaches this will reduce the massive, spiralling cost of product development pipelines. These advances will help establish the molecular engineering rules underlying challenging scientific problems in the life sciences that are currently intractable. The technology advances and the corresponding insight in biology generated will be exploitable in industrial and medical applications, resulting in enhanced capabilities for end-users in biological research, biomarker discovery, diagnostics and drug discovery.
These advances will make a significant contribution to innovation in UK industry, with a 5-10 year timeframe for commercial realisation. e.g. These tools will facilitate the identification of illness in its early stages, minimising permanent damage (10 yrs) and reducing associated healthcare costs. In the context of drug discovery, the ability to fuse the power of AI with molecular technologies that provide insight into the molecular mechanisms of disease, target and biomarker validation and testing for side effects of candidates will radically transform productivity (5-10 yrs). Developments in automation and rapid prototyping will reduce the barrier to entry for new start-ups and turn biology into an information technology driven by data, computation and high-throughput robotics. Technologies such as integrated single cell analysis and label free molecular tracking will be exploitable for clinical diagnostics and drug discovery on shorter time scales (ca.3-5 yrs).
Entrepreneurship & Exploitation: Embedded within the CDT, the DISRUPT tech-accelerator programme will drive and support the creation of a new wave of student-led spin-out vehicles based on student-owned IP.
Wider Community: The outreach, responsible research and communication skill-set of our graduates will strengthen end-user engagement outside their PhD research fields and with the general public. Many technologies developed in the CDT will address societal challenges, and thus will generate significant public interest. Through new initiatives such as the Makerspace the CDT will spearhead new citizen science approaches where the public engage directly in CDT led research by taking part in e.g hackathons. Students will also engage with a wide spectrum of stakeholders, including policy makers, regulatory bodies and end-users. e.g. the Molecular Quarter will ensure the CDT can promote new regulatory frameworks that will promote quick customer and patient access to CDT led breakthroughs.