The Development of Rucaparib/Rubraca®: A Story of the Synergy Between Science and Serendipity

Abstract

The poly(ADP-ribose) polymerase (PARP) inhibitor, Rubraca®, was given its first accelerated approval for BRCA-mutated ovarian cancer by the FDA at the end of 2016, and further approval by the FDA, EMA and NICE followed. Scientists at Newcastle University initiated the early stages, and several collaborations with scientists in academia and the pharmaceutical industry enabled its final development to the approval stage. Although originally considered as a chemo- or radiosensitiser, its current application is as a single agent exploiting tumour-specific defects in DNA repair. As well as involving intellectual and physical effort, there have been a series of fortuitous occurrences and coincidences of timing that ensured its success. This review describes the history of the relationship between science and serendipity that brought us to the current position.

Keywords: PARP; clinical trials; drug development; synthetic lethality.

Figure 1

Accidental synthesis of first “hit” compound, NU1025. During the attempted synthesis of 2-methylbenzoxazole-4-carboxamide, which could exist in the desired anti- conformation or the syn- conformation (left), a molecular rearrangement occurred, resulting in NU1025, a much more potent compound.

Figure 2

Inhibition of cellular poly (ADP-ribose) polymerase (PARP) activity. (A) PARP inhibition by increasing concentrations of AG14699 (rucaparib) following pre-treatment of L1210 cells (30 min) with drug prior to harvesting (red symbols and line) compared with drug added to the permeabilised cells in the reaction mixture (blue). Data are the mean and SD of three replicates from a representative experiment. (B) Stability of PARP inhibition by rucaparib with storage. Cells were exposed to rucaparib for 30 min prior to harvesting and cryopreservation. PARP activity was measured by ³²P NAD⁺ incorporation. Previously unpublished data.

Figure 3

AG14361 is more cytotoxic in XRCC3 mutant irs1SF cells compared to wild-type AA8 Chinese hamster ovary cells (A) but BRCA2 mutant Capan-1 cells are not more sensitive than BRCA wild-type BxPC-3 pancreatic cancer cells (B). Cells were exposed to increasing concentrations of AG14361 for 24 h prior to seeding for colony formation in fresh medium. The insert shows an extended concentration range for pancreatic cell lines. Previously unpublished data pooled from three independent experiments.

Figure 4

Timeline of the development of Rubraca®. Key milestones are indicated at the top of the timeline, the nature of the work undertaken at Newcastle, the funding sources and pharmaceutical companies involved are shown below the timeline.