Approved medicines
Rucaparib (PARP1 inhibitor)
Our work on this medicine combined basic, translational, drug discovery and clinical science.
At a glance:
- Newcastle pioneered PARP1 inhibition
- first-in class PARP inhibitor
- global-first administration of a PARP inhibitor to a patient in Newcastle
- marketed drug for the treatment of ovarian cancer: Rubraca®
We independently established a project to identify the first PARP inhibitors. Collaborating with Agouron Pharmaceuticals and Pfizer we discovered the PARP inhibitor rucaparib. The drug is now marketed as Rubraca®
Rucaparib entered the clinic in 2003. These were Cancer Research UK-sponsored Phase I trials in Newcastle (PI Professor Ruth Plummer). They represented the first administration anywhere of a PARP inhibitor to a cancer patient.
Independent research followed. It revealed a synthetic lethal interaction between PARP inhibition and homologous recombination DNA repair-deficiency. This provided a basis for its examination in BRCA mutated (germline and/or somatic) cancers. The clinical development programme was supported by Clovis Oncology.
Rubraca is now approved in two different indications in ovarian cancer:
- Maintenance treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer whose cancer has come back and who are in response (complete or partial response) to a platinum-based chemotherapy
- Treatment of adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have certain “BRCA” gene mutations, either inherited (germline) or acquired (somatic), and who have been treated with 2 or more chemotherapy medicines for their cancer.
Our work won the inaugural Cancer Research UK Translational Research Team Prize in 2010.
Erdafitinib (FGFR inhibitor)
We pursued the idea of developing a selective FGFR tyrosine kinase inhibitor. This resulted in the clinical development candidate, erdafitinib (JNJ-42756493).
At a glance:
- Astex collaboration
- subsequent research and development by Janssen
- first FGFR kinase inhibitor registration
- approved by the FDA for the treatment of bladder cancer
- now marketed by Janssen as BalversaTM
We established a single-project collaboration with Astex Pharmaceuticals for this purpose. The project discovered compounds that were shown to have very significant antitumour activity in FGF/FGFR-dependent tumour models. These inhibitors formed the basis of a further collaboration with Astex and Janssen. This resulted in the clinical development candidate, erdafitinib (JNJ-42756493).
In April 2019, erdafitinib became the first FGFR tyrosine kinase inhibitor to receive an FDA (USA) approval in patients with locally advanced and unresectable or metastatic urothelial cancer that harboured aberrant forms of FGFR-2 or -3, and who had previously progressed on at least one line of platinum-containing chemotherapy.
The compound is now marketed by Janssen as BalversaTM.
Candidate drugs in early clinical evaluation
We have initiated two other projects that have led to the identification of candidate drugs. They are currently being evaluated in early clinical trials.
ASTX295 (MDM2-p53 antagonist)
Our MDM2-p53 antagonist project was one of the first accepted into our Drug Discovery Alliance with Astex Pharmaceuticals (UK). We structurally-enabled the project, enabling significant potency gains to be realised. Significant additional investment by Astex enabled the joint team to deliver a candidate molecule (ASTX295). It entered Phase I/II clinical development in July 2019.
The compound is being examined in patients with wild-type-TP53 tumours.
DNA-PK inhibitors
We undertook pioneering work to identify inhibitors of DNA-dependent protein kinase (DNA-PK). This includes NU7441 that is currently used as a tool compound in 95 publications.
A collaboration with AstraZeneca revealed the more selective NU5455. Although this was not taken forward as a clinical compound, the collaboration continued. An anilinopurinone-derived inhibitor series was identified from the AstraZeneca compound collection.
AstraZeneca independently optimised the series and declared AZD7648 as a clinical candidate. The compound entered clinical development in October 2019. The aim is to examine its activity in cancer patients when combined with either pegylated liposomal doxorubicin or the PARP-inhibitor olaparib.
Awards and recognition
Emeritus Professor of Cancer Therapeutics Herbie Newell:
- awarded a CBE for services to Medical Research and Drug Development in Queen’s 2019 New Year Honours
- Director of Translational Research at Cancer Research UK (2006 – 2009)
- Interim Executive Director of Clinical and Translational Research at Cancer Research UK (2007-2008)
Awards:
- Prof Griffin: Royal Society of Chemistry’s George and Christine Sosnovsky Award in Cancer Therapy in 2014
- Inaugural Cancer Research UK Translational Research Team Prize in 2010