A new anticancer drug to treat breast and ovarian cancer called rucaparib (Rubraca) has recently been approved by the US Food and Drug Administration. The drug offers hope to a large number of people with an increased genetic risk of developing these types of cancers due to a deficiency of a gene called BRCA. Patients with the BRCA deficiency have been historically difficult to treat.
The project that led to this important discovery was one of the first projects of the Drug Discovery Programme funded by Cancer Research UK that was established at Newcastle University in 1990 involving the School of Chemistry and the Northern Institute for Cancer Research. The team established research on inhibitors of DNA repair enzymes, including an enzyme called poly(ADP-ribose) polymerase (PARP-1). It was later established, that inhibiting PARP-1 was particularly effective in treating tumours with mutated BRCA.
Finding an inhibitor of this enzyme relied on designing a molecule that would displace PARP-1’s natural substrate: nicotinamide adenine dinucleotide (NAD+). The pioneering breakthrough was provided by Professor Bernard Golding in the School of Chemistry. He recognised that binding of NAD+ to PARP-1 requires a specific shape of the NAD+ molecule. This led to the idea that molecules called benzimidazole-4-carboxamides could exist as ‘pseudocycles’ in which the desired shape was fixed by a special type of bond (‘intramolecular hydrogen bond’ – see structures below). By 2000, the synthesis of a range of benzimidazole-4-carboxamides, in a team led by Professor Roger Griffin with Bernard Golding, resulted in the discovery of inhibitors with very high affinity for PARP-1. Further structural modification of benzimidazole-carboxamides led in collaboration with Agouron Pharmaceuticals (San Diego) to rucaparib. The drug was ultimately progressed through late stage clinical trials by Clovis Oncology that led to its approval.
Professor Golding said: “The Newcastle University research on PARP-1 showed how great teamwork between chemical and medical scientists is needed to discover new drugs today.”
Professor Andrew Benniston, Acting Head of School said, “The School of Chemistry is delighted to have been associated with this ground-breaking and internally recognised research.”
White, AW; Almassy, R; Calvert, AH; Curtin, NJ; Griffin, RJ; Hostomsky, Z; Maegley, K; Newell, DR; Srinivasan, S; Golding, BT, Journal of Medicinal Chemistry, 2000, volume 43, pages 4084-4097.
Griffin, RJ; Calvert, AH; Curtin, NJ; Newell, DR; Golding, BT, US patent 6310082 B1.
published on: 7 April 2017