Identification

Name
Talazoparib
Accession Number
DB11760
Type
Small Molecule
Groups
Approved, Investigational
Description

Talazoparib was approved by the FDA for use in germline BRCA mutated, HER2 negative, locally advanced or metastatic breast cancer on October 16, 2018 under the trade name Talzenna [3]. Talzenna was granted approval based on the results of the EMBRACA trial in which talazoparib resulted in a mean 8.6 months progression-free survival time versus physician's choice chemotherapy which resulted in 5.6 months progression-free survival.

Structure
Thumb
Synonyms
  • Talazoparib
External IDs
BMN 673 / BMN-673 / LT-673
Product Ingredients
IngredientUNIICASInChI Key
Talazoparib tosylate02WK9U5NZC1373431-65-2QUQKKHBYEFLEHK-QNBGGDODSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TalzennaCapsule0.25 mg/1OralPfizer Laboratories Div Pfizer Inc2018-10-26Not applicableUs
TalzennaCapsule1 mg/1OralU.S. Pharmaceuticals2018-10-26Not applicableUs
TalzennaCapsule1 mg/1OralPfizer Laboratories Div Pfizer Inc2018-10-26Not applicableUs
Categories
UNII
9QHX048FRV
CAS number
1207456-01-6
Weight
Average: 380.359
Monoisotopic: 380.119715421
Chemical Formula
C19H14F2N6O
InChI Key
HWGQMRYQVZSGDQ-HZPDHXFCSA-N
InChI
InChI=1S/C19H14F2N6O/c1-27-18(22-8-23-27)15-16(9-2-4-10(20)5-3-9)24-13-7-11(21)6-12-14(13)17(15)25-26-19(12)28/h2-8,15-16,24H,1H3,(H,26,28)/t15-,16-/m1/s1
IUPAC Name
(11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-2,3,10-triazatricyclo[7.3.1.0^{5,13}]trideca-1,5,7,9(13)-tetraen-4-one
SMILES
CN1N=CN=C1[C@@H]1[C@H](NC2=C3C1=NNC(=O)C3=CC(F)=C2)C1=CC=C(F)C=C1

Pharmacology

Indication

Talazoparib is indicated for the treatment of deleterious or suspected deleterious germline BRCA mutated, HER2 negative locally advanced or metastatic breast cancer in adults [Label].

Associated Conditions
Pharmacodynamics

Talazoparib prevents PARP-mediated repair of DNA damage in cancer cells, allowing accumulation of damage and PARP-DNA complexes [Label]. Repair related errors by error prone secondary repair pathways may also contribute to the cytotoxicity of talazoparib [2].

Mechanism of action

Talazoparib binds to and inhibits PARP1 and PARP2 at the NAD+ binding site with a Ki of 1.2 and 0.87 nM, respectively [1]. The inhibitory effect on PAR synthesis has an EC50 of 2.51 nM.

TargetActionsOrganism
APoly [ADP-ribose] polymerase 1
inhibitor
Human
APoly [ADP-ribose] polymerase 2
inhibitor
Human
Absorption

Talzenna capsules have a reach peak plasma concentration in 1-2 h [Label]. If taken with a high fat meal, Cmax decreases by 43%, Tmax increases by 1-4 h, and no change occurs in AUC.

Volume of distribution

Talazoparib has a mean apparent volume of distribution of 420 L [Label].

Protein binding

Talazoparib is 74% bound to plasma proteins and independent of drug concentration [Label].

Metabolism

Talazoparib is metabolized via mono-oxidation, dehydrogenation, cysteine conjugation of a mono-desfluoro metabolite, and glucuronide conjugation [Label]. The overall contribution of metabolism to talazoparib elimination is minimal.

Route of elimination

64.7% of talazoparib is excreted in the urine with 54.6% as unchanged drug [Label]. 19.7% is eliminated in the feces with 13.6% as unchanged drug.

Half life

The mean terminal plasma half life of Talzenna capsules is 90 h with a standard deviation of 58 h [Label].

Clearance

The mean apparent oral clearance of talazoparib is 6.45 L/h with an inter-individual variability of 31.1% [Label]. Apparent oral clearance is reduced by 14.4% in patients with mild renal impairment while mild hepatic impairment has no effect. No data is available in patients with moderate to severe renal or hepatic impairment.

Toxicity

Talazoparib is clastogenic due to its pharmacological mechanism [Label]. Talazoparib does not appear to be mutagenic and no data is available on carcinogenicity.

In repeat-dose toxicity studies up to 3-months duration at doses ≥0.04 mg/kg/day in rats and ≥0.01 mg/kg/day in dogs resulted in decreased organ weights, luminal cellular debris, reduced sperm, and degeneration/atrophy in the testis and epididymis [Label]. These doses were equivalent to approximately 1.0 times and 0.2 times normal human exposure. Follicular atresia of the ovary was observed in rats at doses ≥1 mg/kg/day, equivalent to 9.5 times normal human exposure. While no fertility data exists these results suggest a potential for reduced fertility due to talazoparib exposure.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbemaciclibThe serum concentration of Talazoparib can be increased when it is combined with Abemaciclib.
AcetaminophenThe serum concentration of Talazoparib can be increased when it is combined with Acetaminophen.
AfatinibThe serum concentration of Talazoparib can be increased when it is combined with Afatinib.
AlbendazoleThe serum concentration of Talazoparib can be increased when it is combined with Albendazole.
AldosteroneThe serum concentration of Talazoparib can be decreased when it is combined with Aldosterone.
AlectinibThe serum concentration of Talazoparib can be increased when it is combined with Alectinib.
AmiodaroneThe serum concentration of Talazoparib can be increased when it is combined with Amiodarone.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Talazoparib.
AmlodipineThe serum concentration of Talazoparib can be increased when it is combined with Amlodipine.
AmodiaquineThe serum concentration of Talazoparib can be increased when it is combined with Amodiaquine.
Food Interactions
Not Available

References

Synthesis Reference

Wang B, Chu D, Feng Y, Shen Y, Aoyagi-scharber M, Post LE. Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016;59(1):335-57.

General References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]
  2. Javle M, Curtin NJ: The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 2011 Oct 11;105(8):1114-22. doi: 10.1038/bjc.2011.382. [PubMed:21989215]
  3. Talazoparib FDA Approval [Link]
External Links
PubChem Compound
44819241
PubChem Substance
347828114
ChemSpider
28637772
ChEMBL
CHEMBL3137320
HET
2YQ
Wikipedia
Talazoparib
PDB Entries
4pjt / 4pjv / 4und
FDA label
Download (549 KB)
MSDS
Download (25 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Active Not RecruitingTreatmentCancer of the Ovary / Fallopian Tube Cancer / Fallopian Tube Serous Adenocarcinoma / High Grade Ovarian Serous Adenocarcinoma / Malignant Peritoneal Neoplasm / Ovarian Mass / Primary Peritoneal Serous Adenocarcinoma / Stage III Fallopian Tube Cancer AJCC v7 / Stage III Ovarian Cancer AJCC v6 and v7 / Stage III Primary Peritoneal Cancer AJCC v7 / Stage IIIA Fallopian Tube Cancer AJCC v7 / Stage IIIA Ovarian Cancer AJCC v6 and v7 / Stage IIIA Primary Peritoneal Cancer AJCC v7 / Stage IIIB Fallopian Tube Cancer AJCC v7 / Stage IIIB Ovarian Cancer AJCC v6 and v7 / Stage IIIB Primary Peritoneal Cancer AJCC v7 / Stage IIIC Fallopian Tube Cancer AJCC v7 / Stage IIIC Ovarian Cancer AJCC v6 and v7 / Stage IIIC Primary Peritoneal Cancer AJCC v7 / Stage IV Fallopian Tube Cancer AJCC v6 and v7 / Stage IV Ovarian Cancer AJCC v6 and v7 / Stage IV Primary Peritoneal Cancer AJCC v71
1Active Not RecruitingTreatmentBRCA-mutated Solid Tumor / Triple Negative Metastatic Breast Cancer1
1Active Not RecruitingTreatmentMetastatic Cancers / Unspecified Adult Solid Tumor1
1CompletedOtherHuman Volunteers1
1CompletedTreatmentAdvanced Solid Tumors2
1CompletedTreatmentAdvanced or Recurrent Solid Tumors / Ewing's Sarcoma (ES) / Malignant Neoplasm of Pancreas / Neoplasms, Breast / Ovarian Cancer, Epithelial / Prostate Cancer / Small Cell Lung Carcinoma1
1CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia Acute Myeloid Leukemia (AML) / Mantle Cell Lymphoma (MCL) / Myelodysplastic Syndrome1
1CompletedTreatmentTumors, Solid1
1Enrolling by InvitationTreatmentAdvanced or Recurrent Solid Tumors / Neoplasms, Breast1
1Not Yet RecruitingTreatmentEstrogen Receptor Negative / Head and Neck Squamous Cell Carcinoma (HNSCC) / HER2/Neu Negative / Hormone-Resistant Prostate Cancer / Pancreatic Adenocarcinoma Metastatic / Progesterone Receptor Negative / Solid Neoplasms / Stage III Mesothelioma / Stage IIIA Gastric Cancer / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIA Ovarian Cancer / Stage IIIA Small Cell Lung Carcinoma / Stage IIIB Gastric Cancer / Stage IIIb Non-small Cell Lung Cancer / Stage IIIB Ovarian Cancer / Stage IIIB Small Cell Lung Carcinoma / Stage IIIC Gastric Cancer / Stage IIIC Ovarian Cancer / Stage IV Mesothelioma / Stage IV Non-Small Cell Lung Cancer / Stage IV Ovarian Cancer / Stage IV Small Cell Lung Carcinoma / Triple-Negative Breast Carcinoma1
1RecruitingTreatmentAdvanced Malignant Solid Neoplasm / BRCA Rearrangement / BRCA1 Gene Mutation / Brca2 Gene Mutation / Deleterious BRCA1 Gene Mutation / Deleterious BRCA2 Gene Mutation / Metastatic Malignant Solid Neoplasm / Solid Neoplasms / Unresectable Solid Neoplasm1
1RecruitingTreatmentAdvanced Solid Tumors2
1RecruitingTreatmentChildhood Solid Tumors1
1RecruitingTreatmentNeoplasms1
1WithdrawnTreatmentAdult Solid Neoplasm / Estrogen Receptor Negative / Fallopian Tube Serous Neoplasm / HER2/Neu Negative / Ovarian Serous Adenocarcinoma / Ovarian Serous Tumor / Primary Peritoneal Serous Adenocarcinoma / Progesterone Receptor Negative / Recurrent Breast Carcinoma / Recurrent Fallopian Tube Carcinoma / Recurrent Ovarian Carcinoma / Recurrent Primary Peritoneal Carcinoma / Triple-Negative Breast Carcinoma1
1WithdrawnTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Non-Small Cell Lung Carcinoma (NSCLC) / Tumors, Solid1
1, 2Active Not RecruitingTreatmentAdult Solid Neoplasm / Childhood Solid Neoplasm / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Central Nervous System Neoplasm / Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor / Recurrent Malignant Solid Neoplasm / Refractory Central Nervous System Neoplasm1
1, 2RecruitingTreatmentAdvanced Breast Cancer / Advanced Ovarian Cancer / Advanced Solid Tumors / Primary Peritoneal Cancer1
1, 2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (AML)1
2Active Not RecruitingTreatmentBRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Neoplasms, Breast1
2Active Not RecruitingTreatmentCancer, Breast1
2Not Yet RecruitingTreatmentRecurrent Extensive Stage Small Cell Lung Carcinoma / Refractory Extensive Stage Small Cell Lung Carcinoma1
2RecruitingTreatmentATM Gene Mutation / ATR Gene Mutation / BARD1 Gene Mutation / BRCA1 Gene Mutation / Brca2 Gene Mutation / BRIP1 Gene Mutation / CHEK1 Gene Mutation / CHEK2 Gene Mutation / FANCA Gene Mutation / FANCC Gene Mutation / FANCD2 Gene Mutation / FANCF Gene Mutation / FANCM Gene Mutation / NBN Gene Mutation / PALB2 Gene Mutation / RAD51 Gene Mutation / RAD51B Gene Mutation / RAD54L Gene Mutation / Recurrent Squamous Cell Lung Carcinoma / RPA1 Gene Mutation / Stage IV Squamous Cell Lung Carcinoma AJCC v71
2RecruitingTreatmentAdvanced Breast Cancer / HER2/Neu Negative / Triple-Negative Breast Cancer (TNBC)1
2RecruitingTreatmentAdvanced Cancers1
2RecruitingTreatmentGenes, BRCA 1 / Locally Advanced or Metastatic Solid Tumors1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Malignancies / Malignant Neoplasm of Pancreas1
2RecruitingTreatmentMalignancies1
2RecruitingTreatmentProstate Cancer1
2RecruitingTreatmentStage I Breast Carcinoma1
2TerminatedTreatmentCancer of the Ovary1
2WithdrawnTreatmentCancer of the Ovary1
2WithdrawnTreatmentEndometrial Cancers1
2, 3RecruitingTreatmentRecurrent Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma AJCC v71
3Active Not RecruitingTreatmentBRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Neoplasms, Breast1
3RecruitingTreatmentCancer of the Ovary1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral0.25 mg/1
CapsuleOral1 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.101 mg/mLALOGPS
logP2.93ALOGPS
logP2.11ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)9.48ChemAxon
pKa (Strongest Basic)1.66ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area84.2 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity111.27 m3·mol-1ChemAxon
Polarizability35.82 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylquinolines. These are heterocyclic compounds containing a quinoline moiety substituted with a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Phenylquinolines
Direct Parent
Phenylquinolines
Alternative Parents
Phthalazinones / Secondary alkylarylamines / Pyridazinones / Fluorobenzenes / Aralkylamines / Aryl fluorides / Triazoles / Heteroaromatic compounds / Lactams / Azacyclic compounds
show 4 more
Substituents
Phenylquinoline / Phthalazinone / Phthalazine / Fluorobenzene / Halobenzene / Pyridazinone / Secondary aliphatic/aromatic amine / Aralkylamine / Aryl halide / Aryl fluoride
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP1
Uniprot ID
P09874
Uniprot Name
Poly [ADP-ribose] polymerase 1
Molecular Weight
113082.945 Da
References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Nad+ adp-ribosyltransferase activity
Specific Function
Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This ...
Gene Name
PARP2
Uniprot ID
Q9UGN5
Uniprot Name
Poly [ADP-ribose] polymerase 2
Molecular Weight
66205.31 Da
References
  1. Wang B, Chu D, Feng Y, Shen Y, Aoyagi-Scharber M, Post LE: Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-te trahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent. J Med Chem. 2016 Jan 14;59(1):335-57. doi: 10.1021/acs.jmedchem.5b01498. Epub 2015 Dec 23. [PubMed:26652717]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created on October 20, 2016 14:45 / Updated on December 14, 2018 17:14