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]

• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• 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]

• Molecule Alteration: Nonsense; p.Q456* (c.1366C>T)
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• 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.
• In Vivo Model: Male athymic nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting 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]

• Molecule Alteration: Mutation; .
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Nonsense; p.R1443* (c.4327C>T)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Nonsense; p.Q1467* (c.4399C>T)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.C61G (c.181T>G)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.C64Y (c.191G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.M1V (c.1A>G)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.R71G (c.211A>G)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.R71K (c.212G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.R1495M (c.4484G>T)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.E1559K (c.4675G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.D1692N (c.5074G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.M1R (c.2T>G)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.V159M (c.475G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.V211L (c.631G>C)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.R2336H (c.7007G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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) [4]

• Molecule Alteration: Missense mutation; p.R2336P (c.7007G>C)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• 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: 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.