School of Natural and Environmental Sciences

Event items

Tackling metastatic disease – a medicinal chemistry perspective

Chemistry Seminar Series - Prof Andrew Westwell, Cardiff University

Date/Time: Tuesday 19 February 2019, 14:00 - 15:00

Venue: Bedson Building, Room 2.76

Abstract

Andrea Brancale,a Richard Clarkson,b Luke Piggott,a Andrew D. Westwella

aSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB, Wales, U.K.

b European Cancer Stem Cell Research Institute, Cardiff University, CF24 4HQ, Wales, U.K.

E-mail: WestwellA@cf.ac.uk

It is estimated that around 90% of cancer patients die from metastasis (the formation of secondary tumours distant from the original site), rather than their primary disease. Yet there are virtually no efficacious drugs targeting this complex biological phenomenon.[1] Breast cancer provides a useful case in point.

Advances in breast cancer research have established the existence of clinical disease sub-types, each with distinct pathologies, course of disease progression, and response to therapeutic intervention. While survival outcomes have improved dramatically in recent years for oestrogen receptor (ER)-positive disease, sub-types such as “triple-negative” breast cancer (around 15% of cases), present a difficult challenge with standard chemotherapy having little impact on overall survival.

Previous research at Cardiff has established the important role of Bcl3 in metastatic progression of HER2-positive breast cancer within in vitro and in vivo models.[2] Bcl3 is a facilitator protein of the NF-kB signalling system with significant potential as a target for cancer drug design.

At the outset of this project, there were no reported inhibitors of Bcl3. We chose to focus on the Bcl3-p50 protein-protein interaction, generating a pharmacophore model for virtual screening. Subsequent docking and refinement of virtual hit compounds led to the identification of JS6, which exhibited potent (sub-micromolar) inhibitory activity in a range of relevant breast cancer models including an NF-kB reporter cell line and in cell migration assays.

Crucially, JS6 effectively suppressed metastatic progression within in vivo models of metastatic breast cancer. Further pre-clinical development studies are ongoing and will be discussed, including scale-up of chemical synthesis. 

 

[1] Anderson RL et al. (2019) A framework for the development of effective anti-metastatic agents. https://doi.org/10.1038/ s41571-018-0134-8

[2] Wakefield A, Soukupova J, Montagne A, Ranger J, French R, Muller WJ, Clarkson RW (2013). Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors. Cancer Res. 73(2):745-55.