PARP-1 ( IC50 = 144 nM )
BMN-673 selectively binds to PARP and inhibits the base-excision repair pathway, which is PARP-mediated DNA repair of single strand breaks. This increases the rate at which DNA strand breaks accumulate, encourages genomic instability, and ultimately results in apoptosis. BRCA-1 or BRCA-2 mutated cancer cells are specifically killed by BMN 673. In BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM) cells, BMN 673 exhibits single-agent cytotoxicity. In contrast, the IC50 of BMN 673 varies between 90 nM and 1.9 μM in MRC-5 normal human fibroblast and other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes.

BMN-673 selectively binds to PARP and inhibits the base-excision repair pathway, which is PARP-mediated DNA repair of single strand breaks. This increases the rate at which DNA strand breaks accumulate, encourages genomic instability, and ultimately results in apoptosis. BRCA-1 or BRCA-2 mutated cancer cells are specifically killed by BMN 673. In BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM) cells, BMN 673 exhibits single-agent cytotoxicity. In contrast, the IC50 of BMN 673 varies between 90 nM and 1.9 μM in MRC-5 normal human fibroblast and other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes.

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Talazoparib (BMN 673) potently and selectively inhibits PARP1 and PARP2 enzymatic activity, with superior potency compared to veliparib, rucaparib, and olaparib. [1]
In cellular assays using LoVo cells, Talazoparib (BMN 673) inhibited hydrogen peroxide-induced poly (ADP-ribose) (PAR) formation with an EC50 of 2.5 nM, demonstrating intracellular PARP inhibition. [1]
Talazoparib (BMN 673) exhibited selective cytotoxicity against tumor cell lines with deficiencies in homologous recombination (HR) mediated DNA double-strand break repair (DSBR), such as those with mutations in BRCA1, BRCA2, or PTEN. For example, in the BRCA1-mutant cell line SUM149, the survival fraction 50 (SF50) was 8.57 x 10^-6 M, which was >10^5-fold more potent than veliparib. [1]
In BRCA2-deficient Capan-1 cells, Talazoparib (BMN 673) had an IC50 of 5 nM in single-agent cytotoxicity assays. [1]
Unbiased siRNA screening in CAL51 cells identified that silencing genes involved in HR/DSBR (e.g., BRCA1, BRCA2, PALB2, ATM, ATR) profoundly sensitized cells to Talazoparib (BMN 673), confirming its mechanism of synthetic lethality with HR deficiency. [1]
Talazoparib (BMN 673) induced DNA damage biomarkers, such as nuclear γH2AX foci formation, at concentrations as low as 100 pM. [1]
Talazoparib (BMN 673) potentiated the cytotoxic effects of DNA-damaging agents like temozolomide and SN-38 (active metabolite of irinotecan) in vitro. In LoVo cells combined with 200 µM temozolomide, the GI50 for Talazoparib (BMN 673) was 3 nM. [1]
Specificity screening against a panel of receptors, ion channels, and enzymes (including PARG and hERG potassium channel) at 10 µM showed no significant off-target interactions. No significant hERG inhibition was observed at concentrations up to 100 µM. [1]

BMN 673 exhibits >50% oralbioavailability and pharmacokinetic characteristics that permit single-daily dosing in rat pharmacokinetic studies. Daily oral dosing of BMN 673 significantly and dose-dependently increases the antitumor effects of cytotoxic therapies in MX-1 xenograft tumor model studies.

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Oral administration of Talazoparib (BMN 673) as a single agent demonstrated remarkable anti-tumor activity in mouse xenograft models harboring BRCA1 or PTEN deficiencies. [1]
In mice bearing BRCA1-deficient MX-1 tumor xenografts, once-daily (QD) oral dosing of Talazoparib (BMN 673) at 0.33 mg/kg for 28 days resulted in significant tumor growth inhibition, with 4 out of 6 mice achieving a complete response (tumor impalpable). A lower dose of 0.1 mg/kg also showed activity. [1]
Twice-daily (BID) dosing of Talazoparib (BMN 673) (0.165 mg/kg/dose) for 28 days was more effective than QD dosing (0.33 mg/kg/dose) in the MX-1 model, resulting in 6 out of 6 complete responses and no tumor regrowth for 8 weeks post-treatment cessation. [1]
Talazoparib (BMN 673) also inhibited the growth of PTEN-null xenografts (MDA-MB-468 and LNCaP) upon oral administration. [1]
Talazoparib (BMN 673) potentiated the anti-tumor effects of cisplatin and carboplatin in MX-1 xenograft models in a dose-dependent manner. [1]
A single oral dose of Talazoparib (BMN 673) (1 mg/kg) in MX-1 tumor-bearing mice drastically decreased intratumoral PAR levels (a biomarker of PARP inhibition) at 2 and 8 hours post-dose, with partial recovery at 24 hours. [1]

In order to determine the PARP inhibitor Ki, enzyme assays were carried out in 96-well FlashPlate using 0.5 U PARP1 enzyme, 0.25x activated DNA, 0.2 mCi [3H] NAD, and 5 mmol/L cold NAD (Sigma) in a final volume of 50 mL reaction buffer that contained 10% glycerol (v/v), 25 mmol/L HEPES, 12.5 mmol/L MgCl2, 50 mmol/L KCl, 1 mmol/L dithiothreitol (DTT), and 0.01% NP-40 (v/v), and pH 7.6. NAD was added to the PARP reaction mixture, either with or without inhibitors, to start the reaction, and it was then incubated for one minute at room temperature. The reaction was then stopped by adding 50 microliter of ice-cold 20% trichloroacetic acid (TCA) to each well. After the plate was sealed and shaken for an additional 120 minutes at room temperature, centrifugation was performed. Top-Count was used to determine the radioactive signal bound to the FlashPlate. The Michaelis-Menten equation was used to calculate PARP1 Km at different substrate concentrations (ranging from 1 to 100 mmol/L NAD). Using the formula Ki ¼ IC50/[1þ (substrate)/Km], compound Ki was computed from the enzyme inhibition curve. Using the same assay protocol, Km for the PARP2 enzyme and compound Ki were found. However, instead of using 30 ng of PARP2, 0.25x activated DNA, 0.2 mCi [3H] NAD, and 20 mmol/L cold NAD, the reaction was run for 30 minutes at room temperature.

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\n\nPARP enzyme assays[1]
\nThe ability of a test compound to inhibit PARP-1 enzyme activity was assessed using Trevigen’s PARP Assay Kit following manufacturer’s instruction. IC50 values were calculated using GraphPad Prism5 software. For PARP inhibitor Ki determination, enzyme assays were carried out in 96-well FlashPlate with 0.5 unit PARP1 enzyme, 0.25x activated DNA (Trevigen), 0.2 μCi [3H] NAD and 5 μM cold NAD in a final volume of 50 μL reaction buffer containing 10%glycerol(v/v), 25 mM Hepes, 12.5 mM MgCl2, 50 mM KCl, 1 mM DTT and 0.01% NP-40(v/v), pH 7.6. Reactions were initiated by adding NAD to the PARP reaction mixture with or without inhibitors and incubated for 1 min at room temperature. 50 μL of ice-cold 20% TCA was then added to each well to stop the reaction. The plate was sealed and shaken for a further 120 min at RT, followed by centrifugation. Radioactive signal bound to the FlashPlate was determined using TopCount. PARP1 Km was determined using Michaelis–Menten equation from various substrate concentrations (1-100 μM NAD). Compound Ki was calculated from enzyme inhibition curve according to the formula: Ki = IC50/(1+[substrate]/Km). Km for PARP2 enzyme and compound Ki were determined with the same assay protocol except 30 ng PARP2, 0.25x activated DNA, 0.2 μCi [3H] NAD and 20 μM cold NAD were used in the reaction for 30min at room temperature.\n

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\nBiacore binding assay[1]
\nRecombinant human PARP1 (rhPARP1) catalytic domain (residues 662 – 1011) with N-terminal 6XHis-tag was generated in house and used in binding assay for PARP inhibitor interaction using Biacore T200 (GE Healthcare). rhPARP1 was immobilized on a CM5 sensor chip by amine coupling method. Briefly, one flow cell of a CM5 chip was first activated by a 7-min injection at 10 μL/min of freshly prepared 50 mM NHS: 200 mM EDC (1:1) at rate of 10 μL/min. Then rhPARP1 (100 μg/mL, in 10 mM MES pH 6.5) was injected onto the flow cell for 60-sec at 10 μL/min. The remaining active coupling sites were blocked with a 7-min injection of 1M ethanolamine at 10 μL/min. The immobilization buffer contains 10 mM Hepes pH 7.4, 150 mM NaCl, 0.05% Surfectant P20, 5 mM MgCl2, and 0.5 mM TCEP (tris(2-carboxyethyl)phosphine). The immobilization level was ~7600 RU. For binding kinetics measurement, PARP inhibitors at increasing concentrations (12.5, 25, 50, 100, 200 nM) were injected over the chip surface for 60 sec per injection. The exposure was followed by a dissociation phase of 3600 sec in running buffer (immobilization buffer + 1% DMSO) after the last injection. The flow rate was 50 μL/min. After sensorgrams were corrected for signals from a reference flow, kinetics was calculated with Biacore T200 evaluation software ver.1.0.\n

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\nIntracellular PAR formation assay[1]
\nCellular PAR synthesis assay assesses the ability of a test compound to inhibit polymerization of PAR. LoVo human colorectal tumor cells grown in 96-well microtiter plates overnight were pre-treated with increasing concentrations of PARP inhibitors for 30 min before H2O2 was added at a final concentration of 50 mM. After a 5-min treatment at room temperature, cells were fixed for 10 minutes with pre-chilled methanol/acetone(7:3) at −20 °C. Fixed cells were incubated with anti-PAR monoclonal antibody for 60 min, followed by incubation with FITC coupled goat anti-mouse IgG (diluted 1:100) and 1 μg/mL DAPI for 60 min. FITC signal was normalized with DAPI signal, and EC50 values were calculated using GraphPad Prism.\n

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The inhibitory activity of compounds against PARP1 enzyme was assessed using a standard PARP assay kit. Reactions typically contained PARP1 enzyme, activated DNA, a mixture of radiolabeled and unlabeled NAD+ in an appropriate buffer. Reactions were initiated by adding NAD+, incubated briefly at room temperature, and then stopped with trichloroacetic acid (TCA). Radioactive signal incorporation was measured to determine enzyme activity. IC50 values were calculated from inhibition curves. For Ki determination, assays were performed under similar conditions in specialized plates, and Ki was calculated using the Cheng-Prusoff equation based on the determined Km for NAD+. [1]
The binding kinetics of Talazoparib (BMN 673) to the recombinant human PARP1 catalytic domain were determined using surface plasmon resonance (SPR). The PARP1 protein was immobilized on a sensor chip. Increasing concentrations of the inhibitor were injected over the chip surface, and the association and dissociation phases were monitored in real-time. Sensorgrams were analyzed to calculate the association rate (kon), dissociation rate (koff), and equilibrium dissociation constant (KD). [1]

On a panel of eleven SCLC cell lines, BMN 673 has a strong inhibitory effect (IC50=1.7 to 15 nmol/L), all of which fall within ranges that are clinically feasible. Furthermore, there is a correlation between the expression of DNA repair proteins and the activity of the PI3K pathway and sensitivity to BMN673.

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Confocal microscopy[1]
Cells were seeded on coverslips placed in 6-well plates and after 24 hours treated with several concentrations of olaparib or Talazoparib (BMN 673; MDV3800). 24 hours after treatment the cells were fixed in 10% formalin (3.7% PFA) for 1 hour. Cells were permeabilized with 0.2% Triton X-100 in PBS for 20 minutes, treated with 50 μL DNase I (diluted 1/10 in PBS) for 1 hour at 37°C and then blocked with IFF (PBS + 1% BSA and 2% FBS followed by filter sterilization) for 1 hour. The coverslips were then incubated with rabbit anti-γH2Ax primary (Millipore) and mouse anti-RAD51 primary (both 1:1000 in 50μL IFF) overnight at 4°C. The next day cells were incubated with anti-mouse Alexafluor 546 secondary and anti-rabbit Alexafluor 488 secondary (both 1:1000 in 50μL IFF) for one hour. Cells were then washed in PBS containing DAPI 1:10.000 for 10 minutes and attached on glass plates using Vectashield and nail polish. A minimum of four pictures were made of each coverslip using the Leica confocal microscope, and cells were subsequently counted. At least 100 cells were assessed per coverslip, being positive for γH2Ax if they had more than 5 foci per nucleus. The percentage of positive cells was plotted.

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Intracellular PAR formation was measured to assess cellular PARP inhibition. LoVo cells grown in microplates were pre-treated with PARP inhibitors, then exposed to hydrogen peroxide to induce DNA damage and PAR synthesis. Cells were fixed, permeabilized, and stained with an anti-PAR antibody followed by a fluorescent secondary antibody. Fluorescence signal, normalized to a nuclear stain (DAPI), was used to determine the concentration required for 50% inhibition (EC50). [1]
For siRNA screening, CAL51 cells were reverse-transfected with a library of siRNAs targeting 960 genes. After 48 hours, cells were treated with PARP inhibitors at their respective SF80 concentrations or vehicle control. Cell viability was assessed after 5 days using a luminescent ATP-based assay. Drug Effect (DE) Z-scores were calculated to identify siRNAs that sensitized cells to the drug. [1]
Single-agent cytotoxicity was assessed using long-term (10-12 day) cell growth inhibition assays in 96-well plates. Cells were treated with increasing concentrations of PARP inhibitors, with media and compound refreshed periodically. Cell survival was determined using a luminescent ATP-based assay, and IC50/GI50 values were calculated. [1]
Clonogenic survival assays were performed to assess long-term cell reproductive death. Cells were seeded at low density in multi-well plates, treated with PARP inhibitors for 14 days (with periodic media changes), then fixed and stained. Colonies were counted, and surviving fractions were calculated relative to vehicle-treated controls. [1]
Chemosensitization assays were conducted by co-treating cells with a fixed concentration of a cytotoxic agent (e.g., temozolomide) and increasing concentrations of a PARP inhibitor for 5 days. Cell survival was measured, and GI50 values for the combination were determined. [1]
DNA damage response was assessed by immunofluorescence staining for γH2AX foci. Cells grown on coverslips were treated with inhibitors, fixed, permeabilized, and stained with anti-γH2AX antibody and a fluorescent secondary antibody. Nuclei were counterstained. The percentage of cells with more than 5 γH2AX foci per nucleus was quantified using confocal microscopy. [1]

0.33 and 0.1 mg/kg; Oral gavage and twice daily for 28 consecutive days.Nude mice bearing established subcutaneous MX-1 tumor xenografts. \nXenograft experiments[1]
\nFemale athymic nu/nu mice (8-10 week old) were used for all in vivo xenograft studies. Mice were quarantined for at least 1 week before experimental manipulation. Exponentially growing cells (LNcap, MDA-MB-468) or in vivo passaged tumor fragments (MX-1) were implanted subcutaneously at the right flank of nude mice. When tumors reached an average volume of ~150 mm3, mice were randomized into various treatment groups (6-8 mice/group) in each study. Mice were visually observed daily and tumors were measured twice weekly by calliper to determine tumor volume using the formula [length/2] × [width2]. Group median tumor volume (mm3) was graphed over time to monitor tumor growth. In single agent studies, olaparib (100mg/kg), Talazoparib (BMN 673; MDV3800)  (various doses as indicated), or vehicle (10% DMAc, 6% Solutol and 84% PBS) was administered by oral gavage (p.o.), once daily or Talazoparib (BMN 673; MDV3800)  (0.165 mg/kg) twice daily for 28 consecutive days. Mice were continuously monitored for 10 more days after last day of dosing. In cisplatin combination study, Talazoparib (BMN 673; MDV3800) , olaparib, or vehicle was administered p.o. once daily for 8 days starting on day 1. Cisplatin at a dosage of 6 mg/kg or its vehicle (saline) was administered intra-peritoneally (i.p) as a single injection on day 3, 30 minutes after PARP inhibitor was administered. Combination with carboplatin was conducted in a similar way in MX-1 model in which Talazoparib (BMN 673; MDV3800)  was administered p.o. once daily for either 8 days or 5 days and carboplatin was injected i.p. at single dose of 35 mg/kg, 30 min after Talazoparib (BMN 673; MDV3800)  on day 3.[1]

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\nPAR assay in vivo[1]
\nMX-1 tumor xenografts were prepared as described in methods. When tumors reached an average volume of ~150 mm3, olaparib (100 mg/kg), Talazoparib (BMN 673; MDV3800)  (1 mg/kg) or vehicle was administered in a single p.o. dosing. Tumors were harvested at 2, 8 and 24 hours after drug dosing, snap frozen in liquid N2. Tumor tissue was then homogenized in PBS on ice and extracted with lysis buffer (25mM Tris pH 8.0, 150mM NaCl, 5mM EDTA, 2mM EGTA, 25mM NaF, 2mM Na3VO4, 1mM Pefabloc, 1% Triton X-100, and protease inhibitor cocktail) containing 1% SDS. Levels of PAR in the tumor lysates were determined by ELISA using PARP in vivo PD Assay II kit.

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\nFemale athymic nude mice (nu/nu), 8-10 weeks old, were used for xenograft studies. Tumor cells (e.g., MX-1, MDA-MB-468, LNCaP) or tumor fragments were implanted subcutaneously in the flank. When tumors reached an average volume of approximately 150 mm3, mice were randomized into treatment groups (6-8 mice per group). [1]
\nFor single-agent efficacy studies, Talazoparib (BMN 673) was administered orally by gavage, either once daily (QD) or twice daily (BID), at specified doses (e.g., 0.1, 0.165, 0.33 mg/kg) for 28 consecutive days. The vehicle used was 10% DMAc, 6% Solutol, and 84% PBS. Olaparib was dosed orally at 100 mg/kg QD as a comparator. Tumor volumes were measured regularly with calipers. [1]
\nFor combination studies with platinum drugs, mice were treated orally with Talazoparib (BMN 673) or vehicle once daily for 5 or 8 days. Cisplatin (6 mg/kg) or carboplatin (35 mg/kg) was administered intraperitoneally as a single injection on day 3 (for cisplatin) or day 1 (for carboplatin), approximately 30 minutes after the PARP inhibitor dose. [1]
\nFor pharmacodynamic assessment of PARP inhibition in vivo, tumor-bearing mice received a single oral dose of Talazoparib (BMN 673) (1 mg/kg) or olaparib (100 mg/kg). Tumors were harvested at 2, 8, and 24 hours post-dose, snap-frozen, homogenized, and lysed. PAR levels in tumor lysates were quantified using a PAR-specific ELISA. [1]

Absorption, Distribution and Excretion
Following a once-daily oral administration of 1 mg taprazole, the mean [coefficient of variation (CV%)] AUC and peak plasma concentration (Cmax) at steady state were 208 (37%) ng·hr/mL and 16.4 (32%) ng/mL, respectively. The mean (CV%) steady-state trough concentration (Ctrough) was 3.53 (61%) ng/mL. Steady state was reached within 2 to 3 weeks of treatment. The time to peak concentration (Tmax) was 1 to 2 hours. High-fat, high-calorie diets increased the mean Cmax by 46% and the median Tmax by 4 hours from 1 hour, but did not affect the AUC. The primary route of excretion is renal. Approximately 68.7% of the total dose of radiolabeled taprazole was recovered in the urine, of which 54.6% was unchanged. Approximately 19.7% was recovered in the feces, of which 13.6% was unchanged.
The mean apparent volume of distribution of taporabani is 420 L.
The mean apparent oral clearance is 6.45 L/h. The inter-individual variability is 31%.
Metabolism/Metabolites
Taporabani is minimally metabolized in the liver. Metabolic pathways include monooxidation, dehydrogenation, monodefluorination of taporabani via cysteine conjugation, and glucuronide conjugation.
Biological half-life
The mean terminal plasma half-life (± standard deviation) in cancer patients is 90 (±58) hours.
In vitro metabolic studies in rat, dog, and human liver microsomes showed that taporabani (BMN 673) has excellent metabolic stability, with over 90% of the parent compound remaining after 2 hours of incubation at 1 µM concentration. [1] In pharmacokinetic studies in rats, the absolute oral bioavailability of talazoparib (BMN 673) in a 0.5% carboxymethyl cellulose formulation exceeded 40%. [1] Pharmacokinetic properties predict that its half-life in humans is sufficient to support once-daily dosing. [1] In vitro studies have shown that at concentrations up to 10 µM, talazoparib (BMN 673) does not inhibit major human hepatic cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4). [1]

Hepatotoxicity
Elevated serum transaminase levels are common during tprazole treatment, occurring in 33% of patients, but only 1% had transaminase levels exceeding 5 times the upper limit of normal. These elevations are usually transient and without symptoms or jaundice. Similar rates of transaminase elevation were also reported in the control and comparison groups. Clinical use of tprazole is limited, and no cases of acute liver injury with symptoms or jaundice have been identified. Due to limited clinical experience with tprazole and other PARP inhibitors, the likelihood of liver injury is unclear. Probability score: E (Unproven, but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the clinical use of tprazole during lactation. Because tprazole binds to plasma proteins at a rate of 74%, its concentration in breast milk is likely to be low. The manufacturer recommends discontinuing breastfeeding during taprazole treatment and for one month after the last dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
In vitro studies showed that taprazole has a protein binding rate of 74%, independent of concentration.

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In vitro assessment of human ether-a-go-go-related gene (hERG) potassium channels showed that taprazole (BMN 673) at concentrations up to 100 µM had no significant inhibitory effect, suggesting a low risk of causing clinically significant QTc interval prolongation. [1]
In vivo, mice were treated with Talazoparib (BMN 673) as a single oral dose up to 0.33 mg/kg/day for 28 days. Overall, the treatment was well-tolerated, with no observed deaths or significant weight loss. [1]
Talazoparib (BMN 673) in combination with cisplatin resulted in moderate, dose-dependent weight loss in mice (maximum average weight loss of 11% at 1 mg/kg BMN 673 + cisplatin), with one animal death in the highest combined dose group. Animals treated with cisplatin alone experienced a maximum average weight loss of 3%. [1]
Under the test conditions, Talazoparib (BMN 673) in combination with carboplatin did not cause significant weight loss or death. [1]

[1]. Clin Cancer Res . 2013 Sep 15;19(18):5003-15.

[2]. Clin Cancer Res.2014Apr 15;20(8):2237.

Tprazole is an oral small-molecule DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), used to treat certain cases of breast cancer. Elevated serum transaminase levels during tprazole treatment occur at a moderate rate and are suspected of causing rare, clinically significant acute liver injury. Tprazole is an inhibitor of mammalian poly(ADP-ribose) polymerase (PARP), an enzyme responsible for regulating important cellular functions such as DNA transcription and DNA repair. Developed by Pfizer, tprazole was first approved by the U.S. Food and Drug Administration (FDA) in October 2018 and by the European Medicines Agency (EMA) in June 2019. In September 2020, tprazole was approved by Health Canada. Currently, tprazole is used to treat BRCA-mutated breast cancer and HRR-mutated prostate cancer. Tprazole is a poly(ADP-ribose) polymerase inhibitor. The mechanism of action of tprazole is as a poly(ADP-ribose) polymerase inhibitor. Tprazole panib is an orally administered small-molecule DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), an anti-tumor drug used to treat certain types of breast cancer. Elevated serum transaminases are moderately common during tprazole treatment, and it can cause rare, clinically significant acute liver injury. Tprazole panib is an orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor with potential anti-tumor activity. Tprazole panib selectively binds to PARP, blocking the PARP-mediated base excision repair pathway for repairing single-strand DNA breaks. This exacerbates the accumulation of DNA strand breaks, promotes genomic instability, and ultimately leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nucleoproteins, which signal and recruit other proteins to repair damaged DNA and are activated by single-strand DNA breaks.
See also: Tprazole panib tosylate (active ingredient).

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Drug Indications
Talazopanib is indicated for the treatment of adult patients with locally advanced or metastatic breast cancer who have pathogenic or suspected pathogenic germline BRCA mutations (gBRCAm) and are HER2-negative. This indication has been approved by the US FDA, EMA, and Health Canada. In the United States, talazopanib is also used in combination with enzalutamide for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have HRR gene mutations.
Talazopanib monotherapy is indicated for adult patients with locally advanced or metastatic breast cancer who have germline BRCA1/2 mutations and are HER2-negative. Patients should have received anthracycline and/or taxane therapy during (neo)adjuvant, locally advanced, or metastatic treatment unless they are not suitable for treatment with anthracyclines and/or taxanes. Patients with hormone receptor (HR)-positive breast cancer should have received endocrine therapy or be considered unsuitable for endocrine therapy. Treatment of Ewing's sarcoma
Treatment of breast cancer, treatment of prostate cancer
Mechanism of Action
Poly(ADP-ribose) polymerase (PARP) is a multifunctional enzyme involved in important cellular functions such as DNA transcription and DNA repair. PARP recognizes and repairs single-strand breaks (SSBs) in DNA via the base excision repair (BER) pathway. Double-strand breaks (DSBs) in DNA are repaired through homologous recombination mediated by tumor suppressor proteins encoded by BRCA1 and BRCA2. Tprazole is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), including PARP1 and PARP2. In vitro experiments have shown that tprazole has similar affinity to PARP-1 and PARP-2 isoforms. Tprazole inhibits the base excision repair (BER) pathway, leading to the accumulation of unrepaired single-strand breaks (SSBs), which in turn form double-strand breaks (DSBs), the most toxic form of DNA damage. While BRCA-dependent homologous recombination (HR) can repair DSB in normal cells, this repair pathway is defective in cells carrying BRCA1/2 mutations, such as some tumor cells. Inhibition of PARP in cancer cells carrying BRCA mutations leads to genomic instability and apoptosis. This end result, also known as synthetic lethality, refers to the fact that the two defects—PARP activity inhibition and HR-mediated loss of DSB repair—are harmless individually, but together lead to detrimental consequences. By inhibiting PARP, tprazole increases the formation of the PARP-DNA complex, resulting in DNA damage, reduced cell proliferation, and apoptosis.

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Tprazole (BMN 673) is a novel PARP1/2 inhibitor discovered through medicinal chemistry optimization. Its structure is (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazine-3(7H)-one. [1]
The antitumor activity of PARP inhibitors (such as Talazoparib (BMN 673)) is based on the concept of synthetic lethality, selectively killing cancer cells with defects in DNA repair pathways (especially homologous recombination) (e.g., due to BRCA1/2 mutations). [1]
At the time of publication, Talazoparib (BMN 673) is in early clinical development and is undergoing a Phase I clinical trial to evaluate its safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced solid tumors or hematologic malignancies with DNA repair defects. [1]
Talazoparib (BMN 673) Its good metabolic stability, oral bioavailability, and efficacy characteristics suggest that it is a promising candidate to become a new member of the PARP inhibitor class. [1]

C19H14F2N6O

380.35

380.12

C, 60.00; H, 3.71; F, 9.99; N, 22.10; O, 4.21

1207456-00-5

1207456-00-5; 1207456-01-6; 1207454-56-5 (racemic); 1373431-65-2

135742498

White to off-white solid powder

1.898

2

7

2

28

654

2

CN1C(=NC=N1)[C@H]2[C@@H](NC3=CC(=CC4=C3C2=NNC4=O)F)C5=CC=C(C=C5)F

HWGQMRYQVZSGDQ-HOTGVXAUSA-N

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-/m0/s1

(11R,12S)-7-fluoro-11-(4-fluorophenyl)-12-(2-methyl-1,2,4-triazol-3-yl)-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5(13),6,8-tetraen-4-one

Talazoparib (8R,9S); (8R,9S)-LT-673; BMN 673 racemic; BMN673; BMN-673; LT673; LT 673; LT-673; MDV-3800; MDV 3800; MDV3800; trade name: Talzenna

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)