11:30 – 11:45 Dr Wouter Kallemeijn: Exploring protein N-myristoylation in polarized macrophages
11:45 – 12:00 Dr Peter Summers: Studying G-quadruplex DNA using Fluorescence Lifetime Imaging Microscopy
12:00 – 13:00 Main Visiting Speaker: Professor Bernard T. Golding: Understanding DNA Repair Leads to the Anticancer Drug Rucaparib
Abstract:
The focus of the lecture will be on the research that led to the anticancer drug rucaparib (trade name Rubraca) and will show that modern drug discovery and development is a long-haul teamwork. The research that ultimately led to rucaparib started in 1990 with a collaboration between Newcastle University’s School of Chemistry and the Northern Institute for Cancer Research (NICR) based in the Medical School. The resulting team of chemists and medics established research on inhibitors of DNA repair enzymes, with studies of poly(ADP-ribose) polymerase (PARP-1) leading to the first-in-class inhibitor rucaparib of this enzyme, which was granted FDA approval in December 2016 for the treatment of advanced BRCA-mutant ovarian cancer. The involvement of Agouron Pharmaceuticals (San Diego) in the late 1990s was crucial for the ultimate discovery of rucaparib, which is now being developed by Clovis Oncology (Boulder, Colorado).
Rucaparib targets PARP-1 and can be selective for certain cancer cells. The compound was identified as a result of the Newcastle team’s recognition that binding of the substrate NAD+ to PARP-1 requires a specific conformation of the carboxamide group in the nicotinamide moiety. In this conformation the amide carbonyl is anti to the pyridine C-2/C-3 bond, thus enabling the creation of three hydrogen bonds with PARP-1 (2 with C=O and one with NH). This led to the idea of 1H-benzo[d]imidazole-4-carboxamides as ‘pseudocycles’ in which the desired conformation was fixed by an intramolecular hydrogen bond between N3 and one NH of the carboxamide group. The synthesis of a range of 2-substituted benzimidazole-4-carboxamides led by 2000 to the discovery of PARP-1 inhibitors with low nanomolar potency (published in the Journal of Medicinal Chemistry in 2000, also US patent 6310082 B1). Further structural modification of benzimidazole-carboxamides led in collaboration with Agouron Pharmaceuticals (San Diego) to rucaparib. X-ray analysis of PARP-inhibitor complexes by Agouron validated the Newcastle design concept. Rucaparib has been approved by the FDA (2016) and EMA (2018) for the treatment of BRCA-mutant ovarian cancer.
Following Newcastle pioneering research, many pharma companies joined the hunt for PARP-1 inhibitors with two in clinical trials (niraparib and veliparib) that are very clearly based on the benzimidazole-4-carboxamide pharmacophore. The importance of the Newcastle team’s contribution was recognised by the award in 2010 of the first Cancer Research-UK (CRUK) Translational Cancer Research prize to B T Golding and R J Griffin (Chemistry) with A H Calvert, N J Curtin, B Durkacz, D R Newell, R Plummer (NICR).
The lecture will show how synthetic organic chemistry married to an understanding of enzyme mechanism can, with the essential collaboration of pharmacological and clinical colleagues, lead via a long scientific journey to a new anticancer drug.
Biography:
2019 Robert Robinson Award Winner: Awarded to Professor Bernard Golding for broad and substantial contributions to synthetic and mechanistic organic chemistry directed to biochemistry, microbiology and medicine.
After gaining A-levels in chemistry, physics, pure maths and applied maths (the latter taken in hospital after a near fatal motorcycle accident), I studied chemistry at the University of Manchester, after being rejected by three other universities. I graduated with 1st class honours in 1962 and progressed to research at Manchester under the supervision of Rod Rickards. I obtained a PhD in 1965 for the structure determination of natural products including the polyene macrolide antibiotic pimaricin. The award of a Ciba Fellowship enabled postdoctoral research at the ETH Zürich where I joined the vitamin B12 synthesis team under Albert Eschenmoser. My key contribution was to discover a way to execute Eschenmoser’s sulphur-bridging idea to link the 5-membered rings of the corrin system. In October 1967 I was appointed to a lectureship at the University of Warwick where I rose to reader level primarily for my research modelling coenzyme B12-dependent reactions. I moved to Newcastle University in 1983 as professor of organic chemistry, which gave me the opportunity to collaborate with medical scientists and fulfil my ambition to engage seriously in drug discovery. In 1989, I co-founded the anticancer drug discovery group that has become internationally recognised by virtue of its discoveries of inhibitors of numerous cancer-related targets, notably poly(ADP-ribose) polymerase (PARP-1). The PARP research led, in collaboration with Agouron Pharmaceuticals, to rucaparib (Rubraca), which recently acquired FDA and EMA approval for the treatment of BRCA-mutant ovarian cancer. I also introduced the first medicinal chemistry degree course in the UK in 1989 (BSc in chemistry with medicinal chemistry). Since 2006, I have been emeritus professor and senior research investigator at Newcastle and continue to research and teach. I have also co-founded two SMEs (NewChem 2002; BiBerChem 2017), which are both heavily involved in medically related projects.