Repositioning Candidate Details
| Candidate ID: | R1443 |
| Source ID: | DB12332 |
| Source Type: | approved; investigational |
| Compound Type: | small molecule |
| Compound Name: | Rucaparib |
| Synonyms: | Rucaparib |
| Molecular Formula: | C19H18FN3O |
| SMILES: | CNCC1=CC=C(C=C1)C1=C2CCNC(=O)C3=C2C(N1)=CC(F)=C3 |
| Structure: |
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| DrugBank Description: | Rucaparib is a potent mammalian poly(ADP-ribose) polymerase (PARP) 1, 2 and 3 inhibitor with anticancer properties. PPAR is an enzyme that plays an essential role in DNA repair by activating response pathways and facilitating repair , and defects in these repair mechanisms have been demonstrated in various malignancies, including cancer. Regulation of repair pathways is critical in promoting necessary cell death. BRCA genes are tumor suppressor genes mediate several cellular process including DNA replication, transcription regulation, cell cycle checkpoints, apoptosis, chromatin structuring and homologous recombination (HR). Homologous recombination deficiency (HRD), along with PPAR inhibition, is a vulnerability that enhances the cell death pathway when the single mutations alone would permit viability. Ovarian cancer commonly possesses defects in DNA repair pathways such as HRD due to BRCA mutations or otherwise. There are three main types of ovarian cancer: epithelial (90%), germ cell (5%) and sex cord stromal cell (5%). Epithelial ovarian, being the most common, fifth leading cause of cancer-related deaths in women in the United States. Advanced ovarian cancer particularly poses challenges due to reduced therapeutic response rates from standard platinum-based chemotherapy and overall survival rates. Rucaparib has shown to induce cytotoxicity in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes . Of all the BRCA1/2 mutations in ovarian cancer, most are due to germline mutations (18%), and approximately 7% represent somatic mutations acquired within the tumor . The indication of rucaparib as an oral monotherapy in patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer was granted accelerated approval in 2016 for selected patients who have previously received greater than two lines of platinum-based therapy. It is currently marketed in the US under the brand name Rubraca that contains rucaparib camsylate as the active ingredient. The identification of patients who are eligible for rucaparib therapy is performed via *in vitro* diagnostic tests to detect the presence of a deleterious BRCA mutation (germline and/or somatic). The FDA-approved test qualitatively detects sequence alterations in BRCA1 and BRCA2 (BRCA1/2) genes. More information can be found on the FDA Website . While rucaparib is indicated for deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer, there is evidence that its antitumor activity is also clinically effective against ovarian tumors with high homologous recombination deficiency (HRD) loss of heterozygosity (LOH) . |
| CAS Number: | 283173-50-2 |
| Molecular Weight: | 323.371 |
| DrugBank Indication: | Indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib. |
| DrugBank Pharmacology: | Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA . The effect of multiple doses of rucaparib on QTc interval was evaluated in an open-label single-arm study in 56 patients with solid tumors who were administered continuous doses of rucaparib ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean QTcF increase from baseline (90% confidence interval ) in population pharmacokinetics estimated 95% percentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib twice daily was 14.9 msec (11.1-18.7 msec) . |
| DrugBank MoA: | Poly (ADP-ribose) polymerase (PARP) enzymes play a role in DNA repair. PPAR-1 is responsible in repairing single stranded breaks (SSBs) in base excision repair (BER). PARP1 also functions in nonhomologous end-joining (NHEJ) regulation, chromatin remodeling and homologous recombination (HR) DNA repair pathways . When PARP is inhibited, single-strand breaks become double-strand breaks, which are typically repaired via homologous recombination . Pre-existing homologous recombination deficiency (HRD) may occur through mutations in the BRCA1 or BRCA2 genes, which confers persistant cell repair and growth in cancer cells. Rucaparib is an inhibitor of PARP-1, PARP-2, and PARP-3. Via an inhibitory effect on the PARP enzymatic activity, rucaparib decreases the formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death . It is proposed that PARP inhibition specifically targets tumor cells with preexisting HRD, such as those cells possessing mutations in the BRCA1 or BRCA2 genes . Rucaparib induces synthetic lethality by disrupting ingle- and double-strand repair pathways leading to tumor cell death. It is also suggested that PARP inhibition can lead to trapping of PARP-1 enzyme on damaged DNA, effectively preventing continuation of the DNA repair process; defective BRCA1 recruitment to damaged DNA; and activation of alternative DNA repair such as error-prone nonhomologous end joining (NHEJ) or alternative end joining pathways leading to mutations or chromosomal changes and ultimately cell death . |
| Targets: | Poly [ADP-ribose] polymerase 1 antagonist; Poly [ADP-ribose] polymerase 2 antagonist; Poly [ADP-ribose] polymerase 3 antagonist |
| Inclusion Criteria: | Therapeutic strategy associated |
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