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.
Highlights
Rationale for the Development of poly(ADP-ribose) polymerase (PARP) InhibitorsPoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been the most significant addition to the armoury for the treatment of ovarian cancer since the introduction of platinum therapy in the 1970s and represent a paradigm shift in the way cancers may be treated
This is the story of the development of the first PARPi to enter anticancer clinical trials, Rubraca®, formerly known as rucaparib or AG014699, the nomenclature used here largely reflects the name of the drug at the time of use
The story of the development of rucaparib/Rubraca shows the necessary input of intellectual and physical effort needed over a protracted period of time for the successful development of a drug and how luck played a significant role all the way through from the initial hit right through to the clinical development in ovarian cancer
Summary
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been the most significant addition to the armoury for the treatment of ovarian cancer since the introduction of platinum therapy in the 1970s and represent a paradigm shift in the way cancers may be treated This is the story of the development of the first PARPi to enter anticancer clinical trials, Rubraca®, formerly known as rucaparib or AG014699, the nomenclature used here largely reflects the name of the drug at the time of use. The first suggestion of the involvement of PARP in DNA repair was made by Edward Miller in 1975 [4] To test this hypothesis, Purnell and Whish [5] developed the first inhibitors, which were based on the catalytic mechanism of PARP and the observation that the by-product, nicotinamide, exerts some feedback inhibition. Barbara Durkacz in Sydney Shall’s lab, was published in 1980, showing that 3AB prevented the repair of DNA and increased cytotoxicity following exposure to the DNA methylating agent, DMS [6]
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