Therapeutic targeting for ovarian cancer

Lead Research Organisation: Imperial College London
Department Name: Dept of Chemistry

Abstract

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.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/S023518/1 01/10/2019 31/03/2028
2278792 Studentship EP/S023518/1 01/10/2019 30/09/2023 Emily Wright