Medicinal chemists play crucial roles in preclinical cancer drug design and discovery. They work in close collaboration with experts in cancer biology to optimize targeted drug candidates in the hit-to-lead stage of drug discovery through structure-activity relationship (SAR) studies, towards the identification of a potential clinical candidate. Alongside their expertise in compound analogue synthesis and characterization, medicinal chemists are expected to understand and contribute towards areas such as drug target validation; target binding studies; DMPK; and understanding of in vitro/in vivo efficacy assays to identify lead molecule(s) as part of the drug discovery team within areas of unmet medical need [1]. In this presentation, the role of the medicinal chemist will be illustrated through the development of (a) a novel lead BCL3 inhibitory anticancer small molecule [2] and; (b) the discovery of new pro-nucleotide (ProTide) anti-viral approaches [3]. The BCL3 protein is an emerging cancer drug target with a central role in regulating the NF-kB transcription factor pathway and additional signaling pathways such as WNT/b-catenin, within diseases such as advanced (metastatic) breast and colorectal cancer [4]. Phosphoamidate ProTides are a clinically validated pro-nucleotide strategy, originally discovered by McGuigan and co-workers in Cardiff University, that improves nucleoside monophosphate delivery by bypassing the first (rate-determining) phosphorylation step [5].

We built and computationally modelled the interface between BCL3 and its cognate binding partner p50. Following extensive in silico docking, scoring and preliminary laboratory testing of virtual hit molecules, we identified an anthranilic acid derivative (JS6) as a hit compound, exhibiting anti-metastatic activity within in vivo models of breast cancer [2]. Further optimization led to clinical candidate CB1, an orally bioavailable BCL3 inhibitor with an outstanding pre-clinical efficacy profile in a range of breast and colorectal cancer models. CB1 additionally possesses a wide therapeutic window, and PK properties compatible with daily oral dosing as a first-in-class agent for clinical development, backed by a robust IP protection portfolio. In addition, a new multifunctional ProTide discovery platform will be introduced, featuring enhanced potency, reduced potential toxicity, and built-in fluorescence for nucleoside ProTide- and diamidate-based antiviral (HIV) therapeutics [3].

References:

1. Campbell IB, MacDonald SJF, Procopiou PA (2018). Medicinal chemistry in drug discovery in big pharma: past, present and future. Drug Discov. Today 23(2), 291-234.

2. Soukupová J, Bordoni C, Turnham DJ et al. (2021). The discovery of a novel antimetastatic Bcl3 inhibitor. Mol. Cancer Therap. 20(5), 775-786.

3. Kandil SB, Jones KS, Pannecouque C, Westwell AD (2026). Coumarin-stavudine (d4T) novel hybrid ProTides with dual functionality and enhanced anti-HIV activity. Eur. J. Med. Chem. 304, #118543.

4. Seaton G, Smith H, Brancale A, Westwell AD, Clarkson R (2024). Multifaceted roles for Bcl3 in cancer: a proto-oncogene comes of age. Mol. Cancer, 23(1), #7.

5. Kandil S, Pannecouque C, Chapman FM, Westwell AD, McGuigan C (2019). Polyfluoroaromatic stavudine (d4T) ProTides exhibit anti-HIV activity. Bioorg. Med. Chem. Lett; 29, #126721.

Prof. Andrew D. Westwell has been a Professor of Medicinal Chemistry (Teaching and Research) since August 2016 and, as of March 2026, serves as the Head of the School of Pharmacy and Pharmaceutical Sciences at Cardiff University in Wales, UK. Additionally, he has served as an Independent Board Member for the Velindre University NHS Trust since August 2021 and as an Honorary Professor at the Institute of Molecular Medicine & Stem Cell Research at Amity University, India, since March 2023. His research interests are focused on cancer drug design and discovery, as well as the chemical analysis of new psychoactive substances for harm reduction purposes. In particular, his research focuses on the discovery and preclinical development of new molecules targeting cancers with unmet medical needs, such as advanced and metastatic types of colorectal and breast cancer.

Dr. Westwell received his BSc (Hons) in Chemistry in 1990 and his PhD in Organic Chemistry in 1994 from the University of Leeds. Following his doctoral training, he worked as a postdoctoral researcher in the Department of Chemistry at Loughborough University from 1993 to 1996. From 1996 to 2005, he continued his career at the University of Nottingham’s School of Pharmacy, first as a Senior Research Fellow and later as a Cancer Research UK Lecturer. In 2006, he joined Cardiff University as a Senior Lecturer in Medicinal Chemistry and was promoted to Reader from 2013 to 2016. Between 2018 and 2021, he served as the Dean of Research and Innovation for the College of Biomedical and Life Sciences at Cardiff University. Dr. Westwell is the author of 156 publications indexed in the Scopus database, with an h-index of 44 and over 7,500 citations. Furthermore, he has been an inventor on seven international patent applications and was elected a Fellow of the Learned Society of Wales in May 2024.