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Identification
- Summary
Talazoparib is a poly-ADP ribose polymerase inhibitor used to treat HER2-, BRCA mutated locally advanced or metastatic breast cancer and HRR gene-mutated metastatic castration-resistant prostate cancer.
- Brand Names
- Talzenna
- Generic Name
- Talazoparib
- DrugBank Accession Number
- DB11760
- Background
Talazoparib is an inhibitor of mammalian polyadenosine 5’-diphosphoribose polymerases (PARPs), enzymes responsible for regulating essential cellular functions, such as DNA transcription and DNA repair.4
Developed by Pfizer, talazoparib was first approved by the FDA in October 2018 2 and by the EMA in June 2019.5 It was approved by Health Canada in September 2020.6 Talazoparib is currently used in the treatment of BRCA-mutated breast cancer and HRR-mutated prostate cancer.4,6,7
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Talazoparib (DB11760)
- Weight
- Average: 380.359
Monoisotopic: 380.119715421 - Chemical Formula
- C19H14F2N6O
- Synonyms
- Talazoparib
- External IDs
- BMN 673
- BMN-673
- BMN673
- LT 006673
- LT-00673
- LT-673
- MDV-3800
Pharmacology
- Indication
Talazoparib is indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. This indication is approved by the FDA, EMA, and Health Canada.4,6,7
Talazoparib is also indicated in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC).4,7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Hrr gene-mutated (hrrm) metastatic castration-resistant prostate cancer (mcrpc) Regimen in combination with: Enzalutamide (DB08899) •••••••••••• ••••• Treatment of Locally advanced breast cancer •••••••••••• ••••• Treatment of Metastatic breast cancer •••••••••••• ••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Talazoparib is a cytotoxic and anti-tumour agent. In vitro, talazoparib caused cytotoxicity in cancer cell lines that harboured defects in DNA repair genes, including BRCA1 and BRCA2. Talazoparib mediated anti-tumour effects on patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2.2,4
- Mechanism of action
Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes involved in essential cellular functions, such as DNA transcription and DNA repair. PARPs recognize and repair DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway. DNA double-strand breaks (DSBs) are repaired via homologous recombination by tumour suppressor proteins encoded by BRCA1 and BRCA2.3,2
Talazoparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2.4 In vitro, talazoparib binds to PARP-1 and -2 isoforms with similar affinity.2 Inhibition of the BER pathway by talazoparib leads to the accumulation of unrepaired SSBs, which leads to the formation of DSBs, which is the most toxic form of DNA damage. While BRCA-dependent homologous recombination can repair DSBs in normal cells, this repair pathway is defective in cells with BRCA1/2 mutations, such as certain tumour cells.[A246015] Inhibition of PARP in cancer cells with BRCA mutations leads to genomic instability and apoptotic cell death. This end result is also referred to as synthetic lethality, a phenomenon where the combination of two defects - inhibition of PARP activity and loss of DSB repair by HR - that are otherwise benign when alone leads to detrimental results.1,3 By inhibiting PARP, talazoparib increases the formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.4
Target Actions Organism APoly [ADP-ribose] polymerase 1 inhibitorHumans APoly [ADP-ribose] polymerase 2 inhibitorHumans - Absorption
After administration of talazoparib 1 mg orally once daily, the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) ng x hr/mL and 16.4 (32%) ng/mL, respectively. The mean (CV%) steady-state Ctrough was 3.53 (61%) ng/mL.4 Steady state was reached within two to three weeks of therapy.2 The Tmax ranges from one to two hours.4
A high-fat, high-calorie food increased the mean Cmax by 46% and the median Tmax from one to four hours, without affecting the AUC. 4
- Volume of distribution
The mean apparent volume of distribution of talazoparib is 420 L.4
- Protein binding
In vitro, the protein binding of talazoparib is 74% and is independent of talazoparib concentration.4
- Metabolism
Talazoparib undergoes minimal hepatic metabolism. The metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro talazoparib, and glucuronide conjugation.4
- Route of elimination
The major route of elimination is renal excretion. Approximately 68.7% of the total administered radiolabeled dose of talazoparib was recovered in urine, where 54.6% of that dose was in the form of an unchanged drug. About 19.7% of the drug was recovered in feces, with 13.6% of the dose is unchanged.4
- Half-life
The mean terminal plasma half-life (±standard deviation) is 90 (±58) hours in patients with cancer.2,4
- Clearance
The mean apparent oral clearance is 6.45 L/h. The inter-subject variability is 31%.4
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
There is no information available regarding the acute toxicity (LD50) of talazoparib. There is no specific treatment in the event of talazoparib overdose, and symptoms of overdose have not been established. In the event of an overdose, discontinue treatment with talazoparib, consider gastric decontamination, follow general supportive measures, and treat symptomatically.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Talazoparib can be increased when it is combined with Abemaciclib. Abrocitinib The serum concentration of Talazoparib can be increased when it is combined with Abrocitinib. Adagrasib The serum concentration of Talazoparib can be increased when it is combined with Adagrasib. Afatinib The serum concentration of Talazoparib can be increased when it is combined with Afatinib. Alectinib The serum concentration of Talazoparib can be increased when it is combined with Alectinib. - Food Interactions
- Take at the same time every day.
- Take with or without food. A high-fat, high-calorie meal decreases Cmax and delays Tmax, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Talazoparib tosylate 02WK9U5NZC 1373431-65-2 QUQKKHBYEFLEHK-QNBGGDODSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Talzenna Capsule 1 mg Oral Pfizer Canada Ulc Not applicable Not applicable Canada 
Talzenna Capsule 0.5 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2022-01-31 Not applicable US 
Talzenna Capsule 1 mg Oral Pfizer Europe Ma Eeig 2021-02-11 Not applicable EU 
Talzenna Capsule 0.25 mg Oral Pfizer Europe Ma Eeig 2021-02-11 Not applicable EU Talzenna Capsule, liquid filled 0.75 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 2024-04-17 Not applicable US
Categories
- ATC Codes
- L01XK04 — Talazoparib
- Drug Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Substrates
- Enzyme Inhibitors
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Poly (ADP-ribose) polymerase (PARP) inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
- Pyridazines
- Chemical TaxonomyProvided by Classyfire
- 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
- 1,2,4-triazole / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Fluorobenzene show 19 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 9QHX048FRV
- CAS number
- 1207456-01-6
- 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
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
- 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. [Article]
- Hoy SM: Talazoparib: First Global Approval. Drugs. 2018 Dec;78(18):1939-1946. doi: 10.1007/s40265-018-1026-z. [Article]
- Bochum S, Berger S, Martens UM: Olaparib. Recent Results Cancer Res. 2018;211:217-233. doi: 10.1007/978-3-319-91442-8_15. [Article]
- FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
- Pfizer Press Release: European Commission Approves TALZENNA® (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer [Link]
- Health Canada Approved Drug Products: TALZENNA (Talazoparib) Oral Capsules [Link]
- EMA Approved Drug Products: TALZENNA (talazoparib) Oral Capsules [Link]
- External Links
- PubChem Compound
- 44819241
- PubChem Substance
- 347828114
- ChemSpider
- 28637772
- BindingDB
- 50084621
- 2099704
- ChEMBL
- CHEMBL3137320
- ZINC
- ZINC000072318110
- PDBe Ligand
- 2YQ
- Wikipedia
- Talazoparib
- PDB Entries
- 4pjt / 4pjv / 4und / 7kk3 / 7kkn
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Active Not Recruiting Treatment Advanced Malignant Neoplasm / Non-Small Cell Lung Cancer (NSCLC) / Ovarian Cancer / Solid Tumors / Urothelial Cancer 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment MCRPC 1 somestatus stop reason just information to hide 3 Active Not Recruiting Treatment Prostate Cancer 1 somestatus stop reason just information to hide 3 Completed Treatment BRCA 1 Gene Mutation / BRCA 2 Gene Mutation / Breast Neoplasms 1 somestatus stop reason just information to hide 3 Terminated Treatment Ovarian Cancer 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 0.1 mg/1 Capsule Oral 0.1 mg Capsule Oral 0.25 mg/1 Capsule Oral 0.35 mg/1 Capsule Oral 0.5 mg/1 Capsule Oral 0.75 mg/1 Capsule Oral 1 mg/1 Capsule Oral 1.453 mg Capsule, liquid filled Oral 0.1 mg/1 Capsule, liquid filled Oral 0.25 mg/1 Capsule, liquid filled Oral 0.35 mg/1 Capsule, liquid filled Oral 0.5 mg/1 Capsule, liquid filled Oral 0.75 mg/1 Capsule, liquid filled Oral 1.0 mg/1 Capsule Oral 0.25 mg Capsule Oral 1 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9820985 No 2017-11-21 2029-07-27 US US8012976 No 2011-09-06 2029-10-19 US US8735392 No 2014-05-27 2031-10-20 US US8420650 No 2013-04-16 2029-07-27 US US10189837 No 2019-01-29 2031-10-20 US US10780088 No 2020-09-22 2029-07-27 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.101 mg/mL ALOGPS logP 2.93 ALOGPS logP 2.11 Chemaxon logS -3.6 ALOGPS pKa (Strongest Acidic) 9.48 Chemaxon pKa (Strongest Basic) 1.66 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 84.2 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 111.27 m3·mol-1 Chemaxon Polarizability 35.82 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-1eff4346bf91d0ab9a06 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-056r-0009000000-d6852a92f125c7601cbd Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0009000000-ae3f4f2e7eed281bfe79 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-004i-0009000000-ba83b1b6b5be43e9cf9d Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-01ti-0069000000-89f9f29acfc5ca983f20 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-002r-3349000000-673477b0c4c2c7f71c47 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 194.31976 predictedDeepCCS 1.0 (2019) [M+H]+ 196.71535 predictedDeepCCS 1.0 (2019) [M+Na]+ 202.62785 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:17177976, PubMed:18055453, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:20388712, PubMed:21680843, PubMed:22582261, PubMed:23230272, PubMed:25043379, PubMed:26344098, PubMed:26626479, PubMed:26626480, PubMed:30104678, PubMed:31796734, PubMed:32028527, PubMed:32241924, PubMed:32358582, PubMed:33186521, PubMed:34465625, PubMed:34737271). Mediates glutamate, aspartate, serine, histidine or tyrosine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:19764761, PubMed:25043379, PubMed:28190768, PubMed:29954836, PubMed:35393539, PubMed:7852410, PubMed:9315851). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:33186521, PubMed:34874266). Specificity for the different amino acids is conferred by interacting factors, such as HPF1 and NMNAT1 (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:33589610, PubMed:34625544, PubMed:34874266). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 confers serine specificity by completing the PARP1 active site (PubMed:28190768, PubMed:29954836, PubMed:32028527, PubMed:33186521, PubMed:33589610, PubMed:34625544, PubMed:34874266). Also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (PubMed:29954836, PubMed:30257210). Following interaction with NMNAT1, catalyzes glutamate and aspartate ADP-ribosylation of target proteins; NMNAT1 confers glutamate and aspartate specificity (By similarity). PARP1 initiates the repair of DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones (H2BS6ADPr and H3S10ADPr), thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272, PubMed:27067600, PubMed:34465625, PubMed:34874266). HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP1 in order to limit the length of poly-ADP-ribose chains (PubMed:33683197, PubMed:34732825, PubMed:34795260). In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation (PubMed:26344098, PubMed:30356214). Mediates the poly-ADP-ribosylation of a number of proteins, including itself, APLF, CHFR, RPA1 and NFAT5 (PubMed:17396150, PubMed:19764761, PubMed:24906880, PubMed:34049076). In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively (PubMed:27471034). Required for PARP9 and DTX3L recruitment to DNA damage sites (PubMed:23230272). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). PARP1-mediated DNA repair in neurons plays a role in sleep: senses DNA damage in neurons and promotes sleep, facilitating efficient DNA repair (By similarity). In addition to DNA repair, also involved in other processes, such as transcription regulation, programmed cell death, membrane repair, adipogenesis and innate immunity (PubMed:15607977, PubMed:17177976, PubMed:19344625, PubMed:27256882, PubMed:32315358, PubMed:32844745, PubMed:35124853, PubMed:35393539, PubMed:35460603). Acts as a repressor of transcription: binds to nucleosomes and modulates chromatin structure in a manner similar to histone H1, thereby altering RNA polymerase II (PubMed:15607977, PubMed:22464733). Acts both as a positive and negative regulator of transcription elongation, depending on the context (PubMed:27256882, PubMed:35393539). Acts as a positive regulator of transcription elongation by mediating poly-ADP-ribosylation of NELFE, preventing RNA-binding activity of NELFE and relieving transcription pausing (PubMed:27256882). Acts as a negative regulator of transcription elongation in response to DNA damage by catalyzing poly-ADP-ribosylation of CCNT1, disrupting the phase separation activity of CCNT1 and subsequent activation of CDK9 (PubMed:35393539). Involved in replication fork progression following interaction with CARM1: mediates poly-ADP-ribosylation at replication forks, slowing fork progression (PubMed:33412112). Poly-ADP-ribose chains generated by PARP1 also play a role in poly-ADP-ribose-dependent cell death, a process named parthanatos (By similarity). Also acts as a negative regulator of the cGAS-STING pathway (PubMed:32315358, PubMed:32844745, PubMed:35460603). Acts by mediating poly-ADP-ribosylation of CGAS: PARP1 translocates into the cytosol following phosphorylation by PRKDC and catalyzes poly-ADP-ribosylation and inactivation of CGAS (PubMed:35460603). Acts as a negative regulator of adipogenesis: catalyzes poly-ADP-ribosylation of histone H2B on 'Glu-35' (H2BE35ADPr) following interaction with NMNAT1, inhibiting phosphorylation of H2B at 'Ser-36' (H2BS36ph), thereby blocking expression of pro-adipogenetic genes (By similarity). Involved in the synthesis of ATP in the nucleus, together with NMNAT1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257)
- Specific Function
- Chromatin binding
- Gene Name
- PARP1
- Uniprot ID
- P09874
- Uniprot Name
- Poly [ADP-ribose] polymerase 1
- Molecular Weight
- 113082.945 Da
References
- 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. [Article]
- FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:10364231, PubMed:25043379, PubMed:27471034, PubMed:30104678, PubMed:32028527, PubMed:32939087, PubMed:34108479, PubMed:34486521, PubMed:34874266). Mediates glutamate, aspartate or serine ADP-ribosylation of proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of target residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:25043379, PubMed:30104678, PubMed:30321391). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:32939087). Mediates glutamate and aspartate ADP-ribosylation of target proteins in absence of HPF1 (PubMed:25043379). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 conferring serine specificity by completing the PARP2 active site (PubMed:28190768, PubMed:32028527, PubMed:34108479, PubMed:34486521, PubMed:34874266). PARP2 initiates the repair of double-strand DNA breaks: recognizes and binds DNA breaks within chromatin and recruits HPF1, licensing serine ADP-ribosylation of target proteins, such as histones, thereby promoting decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks (PubMed:10364231, PubMed:32939087, PubMed:34108479). HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP2 in order to limit the length of poly-ADP-ribose chains (PubMed:34732825, PubMed:34795260). Specifically mediates formation of branched poly-ADP-ribosylation (PubMed:30104678). Branched poly-ADP-ribose chains are specifically recognized by some factors, such as APLF (PubMed:30104678). In addition to proteins, also able to ADP-ribosylate DNA: preferentially acts on 5'-terminal phosphates at DNA strand breaks termini in nicked duplex (PubMed:27471034, PubMed:29361132)
- Specific Function
- Chromatin binding
- Gene Name
- PARP2
- Uniprot ID
- Q9UGN5
- Uniprot Name
- Poly [ADP-ribose] polymerase 2
- Molecular Weight
- 66205.31 Da
References
- 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. [Article]
- FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR: Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology. Clin Pharmacokinet. 2022 Dec;61(12):1649-1675. doi: 10.1007/s40262-022-01167-6. Epub 2022 Oct 11. [Article]
- Elmeliegy M, Lang I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D: Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours. Br J Clin Pharmacol. 2020 Apr;86(4):771-778. doi: 10.1111/bcp.14178. Epub 2020 Jan 7. [Article]
- FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR: Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology. Clin Pharmacokinet. 2022 Dec;61(12):1649-1675. doi: 10.1007/s40262-022-01167-6. Epub 2022 Oct 11. [Article]
- Elmeliegy M, Lang I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D: Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours. Br J Clin Pharmacol. 2020 Apr;86(4):771-778. doi: 10.1111/bcp.14178. Epub 2020 Jan 7. [Article]
- FDA Approved Drug Products: TALZENNA (talazoparib) capsules, for oral use (June 2023) [Link]
Drug created at October 20, 2016 20:45 / Updated at August 07, 2024 07:52