rucaparib

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Ligands
rucaparib

GtoPdb Ligand ID: 7736

Synonyms: AG-014699 | AG014699 | AG14447 | PF-01367338 | Rubraca®

rucaparib is an approved drug (FDA (2016), EMA (2018))

Comment: Rucaparib is an orally active poly(ADP-ribose)polymerase (PARP) inhibitor with anti-cancer activity [7]. It was developed by Clovis Oncology.
PARP inhibitors are known to enhance efficacy of anti-cancer therapies such as DNA alkylating agents, topoisomerase I poisons, and ionizing radiation.
Note that in the Thomas et al. paper [7], AG014699 refers to the phosphate salt and AG14447 to the parent molecule.
Rucaparib was accepted for FDA priority review for the treatment of advanced ovarian cancer harbouring mutant BRCA (August 2016).
Note: olaparib was the first PARP inhibitor to be approved for clinical use.

View interactive charts of activity data across species

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	3
Hydrogen bond donors	3
Rotatable bonds	3
Topological polar surface area	56.92
Molecular weight	323.14
XLogP	3.25
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	CNCc1ccc(cc1)c1[nH]c2c3c1CCNC(=O)c3cc(c2)F
Isomeric SMILES	CNCc1ccc(cc1)c1[nH]c2c3c1CCNC(=O)c3cc(c2)F
InChI	InChI=1S/C19H18FN3O/c1-21-10-11-2-4-12(5-3-11)18-14-6-7-22-19(24)15-8-13(20)9-16(23-18)17(14)15/h2-5,8-9,21,23H,6-7,10H2,1H3,(H,22,24)
InChI Key	HMABYWSNWIZPAG-UHFFFAOYSA-N

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Summary of Clinical Use
In December 2016, the US FDA granted accelerated approval to rucaparib for treatment of patients with deleterious germline and/or somatic BRCA mutation associated advanced ovarian cancer who have been treated with two or more chemotherapies. Link here to a list of clinical trials assessing rucaparib registered with ClinicalTrials.gov. Phase 2 trial results are published in [6]. In April 2017, the FDA expanded approval to include use of rucaparib as maintenance treatment for recurrent ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to platinum-based chemotherapy. This desision was based on results from clinical trial NCT01968213 which were published in October 2017 [3]. Approval was further expanded by the FDA in April 2018, to include use as a maintenance treatment for epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer that is in complete or partial response to platinum-based chemotherapy (based on results from the ARIEL3 study NCT01968213). The EMA granted approval in May 2018, for the treatment of high-grade, BRCA mutation +ve cancers of the ovary, fallopian tubes and peritoneum that has been responsive to previous platinum-based chemotherapy [5]. In May 2020, the FDA authorised use of rucaparib (through its accelerated approval program) for the treatment of BRCA mutation +ve metastatic castration-resistant prostate cancer (mCRPC; previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy). This approval was based on evidence from the TRITON2 clinical trial NCT02952534, which also evaluated rucaparib's potential in patients with genetic alterations in DNA damage repair genes other than BRCA [1].

Summary of Clinical Use

In December 2016, the US FDA granted accelerated approval to rucaparib for treatment of patients with deleterious germline and/or somatic BRCA mutation associated advanced ovarian cancer who have been treated with two or more chemotherapies. Link here to a list of clinical trials assessing rucaparib registered with ClinicalTrials.gov. Phase 2 trial results are published in [6]. In April 2017, the FDA expanded approval to include use of rucaparib as maintenance treatment for recurrent ovarian, fallopian tube, or primary peritoneal cancer for patients who are in a complete or partial response to platinum-based chemotherapy. This desision was based on results from clinical trial NCT01968213 which were published in October 2017 [3]. Approval was further expanded by the FDA in April 2018, to include use as a maintenance treatment for epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer that is in complete or partial response to platinum-based chemotherapy (based on results from the ARIEL3 study NCT01968213).
The EMA granted approval in May 2018, for the treatment of high-grade, BRCA mutation +ve cancers of the ovary, fallopian tubes and peritoneum that has been responsive to previous platinum-based chemotherapy [5].
In May 2020, the FDA authorised use of rucaparib (through its accelerated approval program) for the treatment of BRCA mutation +ve metastatic castration-resistant prostate cancer (mCRPC; previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy). This approval was based on evidence from the TRITON2 clinical trial NCT02952534, which also evaluated rucaparib's potential in patients with genetic alterations in DNA damage repair genes other than BRCA [1].

Mechanism Of Action and Pharmacodynamic Effects
PARP-1 (poly(ADP-ribose) polymerase 1) inhibitors enhance the efficacy of drugs/therapies which cause DNA damage (eg alkylating agents such as temozolomide , topoisomerase poisons such as topotecan and irinotecan and ionizing radiation) [2,4]. This action helps to promote cancer cell death, by preventing the DNA repair which is required for cell survival. Cells with mutations in other DNA repair enzymes such as BRCA become more dependent on PARP for DNA repair. In such malignant cells, inhibition of PARP may therefore result in cell death due to accumulated therapy-induced DNA damage.

Mechanism Of Action and Pharmacodynamic Effects

PARP-1 (poly(ADP-ribose) polymerase 1) inhibitors enhance the efficacy of drugs/therapies which cause DNA damage (eg alkylating agents such as temozolomide , topoisomerase poisons such as topotecan and irinotecan and ionizing radiation) [2,4]. This action helps to promote cancer cell death, by preventing the DNA repair which is required for cell survival. Cells with mutations in other DNA repair enzymes such as BRCA become more dependent on PARP for DNA repair. In such malignant cells, inhibition of PARP may therefore result in cell death due to accumulated therapy-induced DNA damage.

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT01968213	A Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer	Phase 3 Interventional	Clovis Oncology, Inc.