Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C13H16N4O |
Molecular Weight | 244.2923 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
C[C@@]1(CCCN1)C2=NC3=C(N2)C=CC=C3C(N)=O
InChI
InChIKey=JNAHVYVRKWKWKQ-CYBMUJFWSA-N
InChI=1S/C13H16N4O/c1-13(6-3-7-15-13)12-16-9-5-2-4-8(11(14)18)10(9)17-12/h2,4-5,15H,3,6-7H2,1H3,(H2,14,18)(H,16,17)/t13-/m1/s1
DescriptionSources: http://adisinsight.springer.com/drugs/800028802Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17473206 | https://www.ncbi.nlm.nih.gov/pubmed/26251615
Sources: http://adisinsight.springer.com/drugs/800028802
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17473206 | https://www.ncbi.nlm.nih.gov/pubmed/26251615
Veliparib (ABT-888) is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. AbbVie is developing veliparib for the treatment of cancers. Clinical trials are underway worldwide, investigating veliparib primarily as part of a combination therapy in oncology indications such as brain, colorectal, melanoma, ovarian, prostate and pancreatic cancers.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17473206 | https://www.ncbi.nlm.nih.gov/pubmed/24647572
Curator's Comment: Veliparib is brain penetrant in rodents. No human data available but the drug is studying for treatment of brain tumors https://www.ncbi.nlm.nih.gov/pubmed/24908656 | https://www.ncbi.nlm.nih.gov/pubmed/25682091
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL3105 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17473206 |
5.2 nM [Ki] | ||
Target ID: CHEMBL5366 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17473206 |
2.9 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
800 mg 1 times / day multiple, oral Highest studied dose Dose: 800 mg, 1 times / day Route: oral Route: multiple Dose: 800 mg, 1 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2365 |
DLT: Seizure... Dose limiting toxicities: Seizure (grade 3, 33.3%) Sources: Page: p.2365 |
400 mg 2 times / day multiple, oral MTD Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 9 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 9 Sources: Page: p.2365 |
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400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
DLT: Vomiting, Appetite decreased NOS... Disc. AE: Fatigue, Vomiting... Dose limiting toxicities: Vomiting (grade 3, 8.3%) AEs leading toAppetite decreased NOS (grade 3, 8.3%) Fatigue (grade 3, 8.3%) Nausea (grade 3, 8.3%) discontinuation/dose reduction: Fatigue (25%) Sources: Page: p.1836Vomiting (16.7%) Neutropenia (25%) Nausea (25%) Thrombocytopenia (25%) Anemia (8.3%) Essential tremor (8.3%) |
600 mg 2 times / day multiple, oral Studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.2365 |
DLT: Asthenia, Nausea... Dose limiting toxicities: Asthenia (grade 2, 20%) Sources: Page: p.2365Nausea (grade 3, 20%) Vomiting (grade 3, 20%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Seizure | grade 3, 33.3% DLT |
800 mg 1 times / day multiple, oral Highest studied dose Dose: 800 mg, 1 times / day Route: oral Route: multiple Dose: 800 mg, 1 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: Page: p.2365 |
Vomiting | 16.7% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Fatigue | 25% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Nausea | 25% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Neutropenia | 25% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Thrombocytopenia | 25% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Anemia | 8.3% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Essential tremor | 8.3% Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Fatigue | grade 3, 8.3% DLT |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Nausea | grade 3, 8.3% DLT |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Vomiting | grade 3, 8.3% DLT |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Appetite decreased NOS | grade 3, 8.3% DLT, Disc. AE |
400 mg 2 times / day multiple, oral RP2D Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.1836 |
unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 12 Sources: Page: p.1836 |
Asthenia | grade 2, 20% DLT |
600 mg 2 times / day multiple, oral Studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.2365 |
Nausea | grade 3, 20% DLT |
600 mg 2 times / day multiple, oral Studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.2365 |
Vomiting | grade 3, 20% DLT |
600 mg 2 times / day multiple, oral Studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: Page: p.2365 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.2365 |
PubMed
Title | Date | PubMed |
---|---|---|
ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. | 2007 May 1 |
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Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. | 2007 May 15 |
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A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. | 2008 Aug |
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Poly (ADP-ribose) polymerase activity regulates apoptosis in HeLa cells after alkylating DNA damage. | 2008 Jun |
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Patient perspectives on phase 0 clinical trials. | 2008 Jun 15 |
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Phase 0 trials: an industry perspective. | 2008 Jun 15 |
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Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts. | 2008 Nov 1 |
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Potentiation of temozolomide cytotoxicity by poly(ADP)ribose polymerase inhibitor ABT-888 requires a conversion of single-stranded DNA damages to double-stranded DNA breaks. | 2008 Oct |
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An enzyme-linked immunosorbent poly(ADP-ribose) polymerase biomarker assay for clinical trials of PARP inhibitors. | 2008 Oct 15 |
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Liquid chromatography-mass spectrometric assay for the quantitation in human plasma of ABT-888, an orally available, small molecule inhibitor of poly(ADP-ribose) polymerase. | 2008 Sep 1 |
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The PARP inhibitor, ABT-888 potentiates temozolomide: correlation with drug levels and reduction in PARP activity in vivo. | 2008 Sep-Oct |
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Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. | 2009 Feb |
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94th RSNA Annual Meeting. | 2009 Jan |
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Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. | 2009 Jan 22 |
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Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. | 2009 Jun 1 |
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Phase 0 clinical trials: an answer to drug development stagnation? | 2009 Jun 1 |
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Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms. | 2010 |
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PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. | 2010 Jul 1 |
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Poly(adp-ribose) polymerase inhibitors: a novel drug class with a promising future. | 2010 Mar-Apr |
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Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. | 2010 Oct |
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MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers. | 2011 Apr 1 |
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Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly(ADP-ribose) polymerase. | 2011 Jul |
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The poly(ADP-Ribose) polymerase inhibitor ABT-888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy. | 2011 Jun |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26251615
recommended Phase II dose of single-agent veliparib as 400 mg bid.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23054213
Using colon cancer cell lines significant synergy was observed between Veliparib (ABT-888) and irinotecan at concentrations of ABT-888 as low as 0.125 μM. The level of synergy observed correlated with the degree of PARP1 inhibition as measured biochemically in cell lysates. ABT-888 at concentrations of 0.5-4 μM resulted in synergy with oxaliplatin.
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Classification Tree | Code System | Code | ||
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EU-Orphan Drug |
EU/3/10/830
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FDA ORPHAN DRUG |
542916
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FDA ORPHAN DRUG |
456514
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NCI_THESAURUS |
C62554
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FDA ORPHAN DRUG |
257108
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FDA ORPHAN DRUG |
246607
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FDA ORPHAN DRUG |
295509
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FDA ORPHAN DRUG |
290209
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01O4K0631N
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9211
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CHEMBL506871
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VELIPARIB
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C60768
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912444-00-9
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DB07232
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100000124275
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DTXSID90238456
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WW-28
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SUB32392
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ACTIVE MOIETY
METABOLITE LESS ACTIVE (PARENT)