Drug Information

Drug (ID: DG01198) and It's Reported Resistant Information

• Name: Rucaparib
• Synonyms: RUCAPARIB; 283173-50-2; Rubraca; Rucaparib free base; AG-14447; Rucaparib (free base); UNII-8237F3U7EH; Kinome_3180; 8-Fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-one; 8237F3U7EH; 283173-50-2 (free base); 8-Fluoro-2-(4-((methylamino)methyl)phenyl)-1,3,4,5-tetrahydro-6H-azepino(5,4,3-cd)indol-6-one; 8-FLUOR-2-{4-[(METHYLAMINO)METHYL]FENYL}-1,3,4,5-TETRAHYDRO-6HAZEPINO[5,4,3-CD]INDOOL-6-ON; 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one; 6H-Pyrrolo[4,3,2-ef][2]benzazepin-6-one,8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-; 8-FLUORO-2-(4-((METHYLAMINO)METHYL)PHENYL)-4,5-DIHYDRO-1H-AZEPINO[5,4,3-CD]INDOL-6(3H)-ONE; C19H18FN3O; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one; Rucaparib [USAN:INN]; PF 01367338; 8-Fluoro-2-[4-[(methylamino)methyl]phenyl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one; RPB; Rucaparib (USAN/INN); Rucaparib(AG-014447); SCHEMBL844585; GTPL7736; CHEMBL1173055; CHEBI:94311; ZINC25958; DTXSID10182563; CHEBI:134689; BCP07633; EX-A2700; BDBM50446130; HY-10617A; NSC756644; s4948; AKOS015898427; AG14447; DB12332; NSC-756644; SB16538; NCGC00263173-01; NCGC00263173-03; NCGC00263173-09; NCGC00263173-13; 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-9-one; 6H-Azepino(5,4,3-cd)indol-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-(4-((methylamino)methyl)phenyl)-; 6H-Pyrrolo(4,3,2-ef)(2)benzazepin-6-one, 8-fluoro-1,3,4,5-tetrahydro-2-(4-((methylamino)methyl)phenyl)-; AC-24390; AS-74779; FT-0696622; A14182; C74459; D10079; Rucaparib; AG 014699; PF-01367338; A856084; Q7376558; BRD-K88560311-011-01-4; 6-fluoro-2-[4-(methylaminomethyl)phenyl]-3,10-diazatricyclo[6.4.1.0^{4,13]trideca-1,4,6,8(13)-tetraen-9-one; 6-fluoro-2-{4-[(methylamino)methyl]phenyl}-3,10-diazatricyclo[6.4.1.0 ,(1)(3)]trideca-1,4,6,8(13)-tetraen-9-one; 6H-Pyrrolo[4,3,2-ef][2]benzazepin-6-one,8-fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]; 8-fluoro-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-1-one
• Indication:
  In total 2 Indication(s)
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
• Target: Poly [ADP-ribose] polymerase (PARP); NOUNIPROTAC; [1]
• Formula: C19H18FN3O
• IsoSMILES: CNCC1=CC=C(C=C1)C2=C3CCNC(=O)C4=C3C(=CC(=C4)F)N2
• 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)
• InChIKey: HMABYWSNWIZPAG-UHFFFAOYSA-N
• PubChem CID: 9931954
• ChEBI ID: CHEBI:94311
• TTD Drug ID: D01SHZ
• INTEDE ID: DR1449
• DrugBank ID: DB12332

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.65 Å; PDB: 6BKX
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.88 Å; PDB: 4UMX

RMSD: 3.46; TM score: 0.85834; Amino acid change: R132H

• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; Ovary; Homo sapiens (Human); CVCL_D3DY
• In Vitro Model: IDH1 cells; Ovary; Homo sapiens (Human); CVCL_D3DY
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Colorectal cancer [ICD-11: 2B91]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: AT-rich interactive domain-containing protein 1A (ARID1A) [3]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: HMEC cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: ARID1A-knockout (Q456*/Q456*) cells; N.A.; N.A.; N.A.
• In Vivo Model: Male athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; ChIP assay
• Experiment for Drug Resistance: Tumor volume measurement assay

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [1]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Here, we describe HRD mechanisms leading to both platinum and rucaparib sensitivity (BRCA mutation, RAD51C/D alterations, and high BRCA1 promoter methylation) and summarize two important cross-resistance mechanisms: BRCA reversion mutations, and loss of BRCA1 methylation described here for the first time using archival and screening clinical specimens.

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [4]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Mutations; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: Whole exome sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Immunohistochemical staining assay; Multidrug resistance activity assay; Neutral comet assay
• Mechanism Description: Olaparib-resistant BRCA1m OvCa cells show greater sensitivity to niraparib and rucaparib relative to other PARPis. Niraparib and rucaparib demonstrated greater cytotoxicity and reduced RF speed compared to the other three PARPis, likely due to the higher levels of SSB induction.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.C61G (c.181T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.C61G (c.181T>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.C64Y (c.191G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.C64Y (c.191G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1V (c.1A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.M1V (c.1A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R71G (c.211A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.R71G (c.211A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R71K (c.212G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.R71K (c.212G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.M1I (c.3G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Nonsense; p.R1443* (c.4327C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The nonsense p.R1443* (c.4327C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Nonsense; p.Q1467* (c.4399C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The nonsense p.Q1467* (c.4399C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R1495M (c.4484G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.R1495M (c.4484G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E1559K (c.4675G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.E1559K (c.4675G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.D1692N (c.5074G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.D1692N (c.5074G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1R (c.2T>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.M1R (c.2T>G) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.M1I (c.3G>T) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.V159M (c.475G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.V159M (c.475G>A) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.V211L (c.631G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.V211L (c.631G>C) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R2336H (c.7007G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.R2336H (c.7007G>A) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [5]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R2336P (c.7007G>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; N.A.
• Mechanism Description: The missense mutation p.R2336P (c.7007G>C) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

References

• Ref 1: Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2) .Nat Commun. 2021 May 3;12(1):2487. doi: 10.1038/s41467-021-22582-6. 10.1038/s41467-021-22582-6
• Ref 2: 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivitySci Transl Med. 2017 Feb 1;9(375):eaal2463. doi: 10.1126/scitranslmed.aal2463.
• Ref 3: ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP InhibitorsCancer Discov. 2015 Jul;5(7):752-67. doi: 10.1158/2159-8290.CD-14-0849. Epub 2015 Jun 11.
• Ref 4: Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant BRCA1-Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge. Cells. 2024 Nov 7;13(22):1847.
• Ref 5: Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trialLancet Oncol. 2017 Jan;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. Epub 2016 Nov 29.