Talazoparib (BMN 673)

Catalog No.S7048 Synonyms: LT-673

Talazoparib (BMN 673) Chemical Structure

Molecular Weight(MW): 380.35

Talazoparib (BMN 673) is a novel PARP inhibitor with IC50 of 0.57 nM for PARP1 in a cell-free assay. It is also a potent inhibitor of PARP-2, but does not inhibit PARG and is highly sensitive to PTEN mutation. Phase 3.

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Cited by 12 Publications

6 Customer Reviews

  • Western blot assessment of effects on PAR, PARP, and dsDNA breaks mediated by IMMU-132 plus PARPi in TNBC tumor lines. Cells were plated overnight in 6-well plates before the addition of chemotherapeutics. After a 24-hour incubation, cells were harvested and cell lysates resolved and transferred for Western analysis as described in Materials and Methods. PAR and FL-PARP levels were determined on the same gel. Assessment of dsDNA breaks (p-H2A.X) was calculated as ratios relative to untreated control (Unt) normalized to b-actin protein loading control (Dp-H2A.X). B, HCC1806 cells exposed to rucaparib (Ruc) and IMMU-132 or to (C) talazoparib (Tala) and IMMU-132.

    Clin Cancer Res, 2017, 23(13):3405-3415. Talazoparib (BMN 673) purchased from Selleck.

    DNA damage persists on withdrawal of PARPi in RNASEH2AKO cells. Wild-type and RNASEH2AKO HeLa cells were treated with talazoparib and released into fresh medium for the indicated times before being processed for γ-H2AX immunofluorescence and propidium iodide (PI) staining. The γ-H2AX immunofluorescence (pseudocolor plots) and cell cycle (histograms) FACS profiles shown are representative of three biologically independent experiments.

    Nature, 2018, 559(7713):285-289. Talazoparib (BMN 673) purchased from Selleck.

  • MDA-MDA-MB-231 and BT549 cells were treated with 10 μM olaparib or 10 nM talazoparib for 24 hours, and subjected to immunoblotting with the indicated antibodies. PD-L1 knockout (K/O) cells were included as a negative control.

    Clin Cancer Res, 2017, 23(14):3711-3720. Talazoparib (BMN 673) purchased from Selleck.

    PARP inhibition prevents adhesion to and migration of monocytes across BMVEC monolayers preserving the barrier. Primary human monocytes were treated for 24 h with PARPi (AIQ, olaparib, EB47, talazoparib), calcein-labeled, washed, and then added to BMVEC monolayers (untreated or treated for 24 h with TNFα). Treatments were removed prior to the addition of monocytes. Adhesion to (a) and migration of (b) monocytes across blood-brain barrier models were measured and are presented as fold difference compared to TNFα-only control (mean ± SEM) for each treatment from at least quadruplicate determinations, which was assigned a value of 1 (7600 relative fluorescent units for adhesion or equivalent to 37 migrated cells). *P < 0.05, **P < 0.01 indicate significance vs. non-treated. TEER, an indicator of barrier integrity, was continuously measured in BMVEC monolayers treated with or without TNFα following the addition of primary human monocytes that had been treated with PARPi.

    J Neuroinflammation, 2016, 13(1):254.. Talazoparib (BMN 673) purchased from Selleck.

  • BT-549 cells reconstituted with Vet, WT, 336* or PTEN WT HP1aKD were treated with BMN673. Relative cell viability was determined by MTT assay. The results were presented as mean of 3 independent experiments. Error bars indicate s.d.

    Cell Cycle, 2015, 14(14): 2323-32. Talazoparib (BMN 673) purchased from Selleck.

    We treated the FA defective and control lung cancer cell lines H1299D2-down/H1299E and A549D2 down/A549E with BMN673 (0.5 µM). MTT assay was used for the cell viability analysis and an averaged absorbance was recorded 24, 48 and 72 h post treatment.

    Front Oncol, 2014, 4: 368. Talazoparib (BMN 673) purchased from Selleck.

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Choose Selective PARP Inhibitors

Biological Activity

Description Talazoparib (BMN 673) is a novel PARP inhibitor with IC50 of 0.57 nM for PARP1 in a cell-free assay. It is also a potent inhibitor of PARP-2, but does not inhibit PARG and is highly sensitive to PTEN mutation. Phase 3.
Features Most potent and selective PARPi reported thus far.
Targets
PARP1 [1]
(Cell-free assay)
0.57 nM
In vitro

BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. BMN 673 selectively kills cancer cells with BRCA-1 or BRCA-2 mutations. BMN 673 demonstrates single-agent cytotoxicityin BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblastand other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of BMN 673 ranges between 90 nM and 1.9 μM. [1] In cultured human cancer cells, BMN 673 also significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
BR5FVB1-Akt MnyxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYqwMlEuOTByIH7N MljGNlQwPDhxN{KgbC=> MVTpcohq[mm2czDj[YxtKHC{b3zp[oVz[XSrb36g[I9{\SCmZYDlcoRmdnSueR?= M2XWNlI3ODR5Nkm3
BR5FVB1-Akt MUnBdI9xfG:|aYOgRZN{[Xl? MVWwMlEuOTByIH7N MV23NkBp M13TdYlv\HWlZYOgZZBweHSxc3nz MlzxNlYxPDd4OUe=
Capan-1 NWDMTYh[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYqxN4F1UUN3ME2xOk4x6oDLwsJihKk2NjUkgJpCuW3DqA>? NWnmeJQ4OjV6NkS1PVA>
MIA PaCa-2 MUHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFXLdGpKSzVyPUW4MlI{6oDLwsJihKk5NjIkgJpCuW3DqA>? NVnPd3k{OjV6NkS1PVA>
RD NW\WcZBjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mli1TWM2OD16Lkegcm0> MVOyOVI3OzV|OR?=
Rh41 MnvJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGPZe|VKSzVyPUiuNUBvVQ>? MUCyOVI3OzV|OR?=
Rh18 NUL5[Gc5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVH4Z2l{UUN3ME20Mlkhdk1? MVeyOVI3OzV|OR?=
Rh30 NUexNoc2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEHPN25KSzVyPUOxMlEhdk1? MkHSNlUzPjN3M{m=
BT-12 NVztOI9mT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NG\1S2VKSzVyPvMAjVEtODByIH7N MX[yOVI3OzV|OR?=
CHLA-266 Mo[1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWDVe5ZyUUN3ME9ihKkyNDByMDDuUS=> MmHONlUzPjN3M{m=
TC-71 NV75Xo9ET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Ml75TWM2OD1|Lkegcm0> MmX0NlUzPjN3M{m=
CHLA-9 NV\UR2ZuT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1LmfGlEPTB;OD6yJI5O MoDHNlUzPjN3M{m=
CHLA-10 MkCwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVvJR|UxRTZ5Lkigcm0> MnnTNlUzPjN3M{m=
CHLA-258 NEX2OWdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWTqb3Q1UUN3ME20MlYhdk1? NG\wNpgzPTJ4M{WzPS=>
SJ-GBM2 NFrBVItIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVPJR|UxRTF4LkKgcm0> MViyOVI3OzV|OR?=
NB-1643 M1Xic2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NXH2enFlUUN3ME2xPE41KG6P NGi2TZMzPTJ4M{WzPS=>
NB-EBc1 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MV;JR|UxRTJ3Lkigcm0> NED2O|czPTJ4M{WzPS=>
CHLA-90 M3HLRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF\UUXVKSzVyPvMAjVEtODByIH7N MWKyOVI3OzV|OR?=
CHLA-136 NITpVVdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXfT[XN5UUN3ME2xOE4zKG6P NIXofJMzPTJ4M{WzPS=>
NALM-6 Moj4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2rkfWlEPTB;NEmgcm0> NETkUVUzPTJ4M{WzPS=>
COG-LL-317 M{jGXmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFWzZnNKSzVyPUmuOEBvVQ>? NUjDNnJROjV{NkO1N|k>
RS4;11 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M33IOGlEPTB;NUKuOkBvVQ>? MUSyOVI3OzV|OR?=
MOLT-4 M3\6RWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWPVN5MzUUN3ME2xOk43KG6P MmDFNlUzPjN3M{m=
CCRF-CEM NV7jfZNjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWXXfFN3UUN3ME22PVcvOyCwTR?= NWqwRpZFOjV{NkO1N|k>
Kasumi-1 MVPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHn6VIJKSzVyPUe4Ok4zKG6P NU\Db4VyOjV{NkO1N|k>
Karpas-299 NWG4OYdDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYDJR|UxRTd3Lkegcm0> M1:5SVI2OjZ|NUO5
Ramos-RA1 NXGzOFBWT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWPJR|UxRTZ6LkOgcm0> NIPCUG4zPTJ4M{WzPS=>
DT40 NHXQdI5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4ryTGlEPTB;NDDuUS=> NEj3WpMzPDN3NkixNy=>
DU145 Mlz5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUm1NGxZUUN3ME2xNUBvVQ>? MonVNlQ{PTZ6MUO=
H209 M{\rNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1fhU2lEPTB;MT63JI5O NHflT3IzPDB5N{O1NC=>
H1048 NI\3V2RIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVrJR|UxRTJwMjDuUS=> M{XoN|I1ODd5M{Ww
H524 M{nUZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoOzTWM2OD1|LkGgcm0> MlfDNlQxPzd|NUC=
H1930 MmrlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3vFUGlEPTB;ND6xJI5O NXjFNpF3OjRyN{ezOVA>
H69 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4DZbWlEPTB;NT6yJI5O MXGyOFA4PzN3MB?=
H2081 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXTJR|UxRTZwMzDuUS=> NH7pXlIzPDB5N{O1NC=>
H2107 MnrMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYX4e5QyUUN3ME23MlMhdk1? MUCyOFA4PzN3MB?=
H1092 MnPNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlfLTWM2OD16Lkmgcm0> NIjWWGozPDB5N{O1NC=>
DMS-79 M4DsRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIW2[VlKSzVyPUmuN{BvVQ>? NXnxTW9sOjRyN{ezOVA>
H446 NYHpVHhiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnO2TWM2OD1zMzDuUS=> NWDyVWw5OjRyN{ezOVA>
COR-L279 NWm3UXpbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFzQRYZKSzVyPUG1JI5O NV;TNJNzOjRyN{ezOVA>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
cleaved-PARP / cleaved-caspase3 / γ-H2AX; 

PubMed: 29158830     


Western Blot data testing protein expression after treatment with Olaparib, Niraparib, and Talazoparib on Brca1-deficient cell line in W0069 cells.

pKAP1 / pChk2 / pChk1; 

PubMed: 28947502     


Western blot images (representative from 3 independent experiments) showing the impact of a 24 hour pre-treatment with TAL ± TMZ on DNA damage signaling in U251 (MGMT-low) and T98G (MGMT-high) cells. 

PD-L1; 

PubMed: 28167507     


MDA-MDA-MB-231 and BT549 cells were treated with 10 μM olaparib or 10 nM talazoparib for 24 hours, and subjected to immunoblotting with the indicated antibodies. PD-L1 knockout (K/O) cells were included as a negative control. 

p-ATM; 

PubMed: 30472087     


Western blot analysis of the DNA damage sensors ATM, p-ATM (Ser1981), CHK1, p-CHK1 (Ser317), CHK2 and p-CHK2 (Thr68) in MV4-11 and HL-60 cells. GAPDH served as a loading control.

29158830 28947502 28167507 30472087
Growth inhibition assay
Cell viability; 

PubMed: 29158830     


Measured dose response curve and IC50 of Talazoparib in W780 and W0069 cells.

29158830
Immunofluorescence
cleaved PARP / 53BP1; 

PubMed: 28958991     


Cleaved-PARP and 53BP1 expression. Representative images with 10× objective from high-content imaging of control cells in the left column, and cells treated with veliparib, olaparib, and talazoparib in three right columns. 53BP1 expression is seen in: A, HCC1143; B, MDAMB231; and C, HCC1806. Blue represents nuclear staining and pink foci represent 53BP1 foci. Cleaved-PARP expression is seen in D, HCC1143 and E, HCC1806. Blue represents nuclear staining and green represents cleaved-PARP expression.

RAD51; 

PubMed: 30621214     


(A) MCF7 and (B) MCF7-T cells were treated with either 100 nM tamoxifen (Tamox) or 1 nM talazoparib (Talaz) for 72 h, alone and in combination. 24 h post treatment RAD51 foci formation assay was performed. Scale bar: 20 µm.

28958991 30621214
In vivo In rat pharmacokinetic studies, BMN 673 displays >50% oralbioavailability and pharmacokinetic properties that enable singledaily dosing. In MX-1 xenograft tumor model studies, daily oral dosingof BMN 673 significantly enhances the antitumor effects ofcytotoxic therapies in a dose-dependent manner. [2]

Protocol

Animal Research:

[2]

+ Expand
  • Animal Models: MX-1 model (BRCA-1 deficient)
  • Formulation: --
  • Dosages: 0.33 mg/kg/day, once daily
  • Administration: Oral
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 38 mg/mL warmed (99.9 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 380.35
Formula

 

C19H14F2N6O
 
CAS No. 1207456-01-6
Storage powder
in solvent
Synonyms LT-673

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03875313 Recruiting Solid Tumor|Clear Cell Renal Cell Carcinoma|TNBC - Triple-Negative Breast Cancer|Colorectal Cancer|CRC|RCC|ccRCC Calithera Biosciences Inc March 2019 Phase 1|Phase 2
NCT03875313 Recruiting Solid Tumor|Clear Cell Renal Cell Carcinoma|TNBC - Triple-Negative Breast Cancer|Colorectal Cancer|CRC|RCC|ccRCC Calithera Biosciences Inc March 2019 Phase 1|Phase 2
NCT03672773 Recruiting Recurrent Extensive Stage Small Cell Lung Carcinoma|Refractory Extensive Stage Small Cell Lung Carcinoma Jonsson Comprehensive Cancer Center|Translational Research in Oncology|National Cancer Institute (NCI) October 31 2018 Phase 2
NCT03672773 Recruiting Recurrent Extensive Stage Small Cell Lung Carcinoma|Refractory Extensive Stage Small Cell Lung Carcinoma Jonsson Comprehensive Cancer Center|Translational Research in Oncology|National Cancer Institute (NCI) October 31 2018 Phase 2
NCT03637491 Recruiting Pancreatic Cancer|Non-Small Cell Lung Cancer|Cancer Pfizer|Array BioPharma August 15 2018 Phase 2
NCT03499353 Recruiting Early Breast Cancer Pfizer August 27 2018 Phase 2

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Frequently Asked Questions

  • Question 1:

    Which solvent do you recommend to dilute the inhibitor for in vivo study in mice?

  • Answer:

    BMN673 (S7048) can be dissolved in vehicle (10% DMAc, 6% Solutol, and 84% PBS) according to the paper: http://clincancerres.aacrjournals.org/content/19/18/5003.full. Quote from Method and Material section "Xenograft experiments: BMN 673 (various doses as indicated), or vehicle (10% DMAc, 6% Solutol, and 84% PBS) was administered by oral gavage"

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID