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.

体外活性：BMN-673 选择性结合 PARP，并通过碱基切除修复途径阻止 PARP 介导的单链 DNA 断裂的 DNA 修复。这会增强 DNA 链断裂的积累，促进基因组不稳定并最终导致细胞凋亡。 BMN 673 选择性杀死具有 BRCA-1 或 BRCA-2 突变的癌细胞。 BMN 673 在 BRCA-1 突变体（MX-1，IC50 = 0.3 nM）和 BRCA-2 突变细胞（Capan-1，IC50 = 5 nM）中表现出单药细胞毒性。相比之下，在 MRC-5 正常人成纤维细胞和其他具有野生型 BRCA-1 和 BRCA-2 基因的肿瘤细胞系中，BMN 673 的 IC50 范围在 90 nM 至 1.9 μM 之间。在培养的人类癌细胞中，BMN 673 还显着增强替莫唑胺和 SN-38 的细胞毒性功效。脱靶分子筛选未发现此类 PARP 抑制剂具有显着的非特异性活性。激酶测定：对于 PARP 抑制剂 Ki 测定，在 96 孔 FlashPlate 中进行酶测定，最终体积中含有 0.5 U PARP1 酶、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 5 mmol/L 冷 NAD(Sigma) 50 mL 反应缓冲液，含有 10% 甘油 (v/v)、25 mmol/L HEPES、12.5 mmol/L MgCl2、50 mmol/L KCl、1 mmol/L 二硫苏糖醇 (DTT) 和 0.01% NP-40 (v /v），pH 7.6。通过将 NAD 添加到含有或不含抑制剂的 PARP 反应混合物中来引发反应，并在室温下孵育 1 分钟。然后向每孔中加入50微升冰冷的20%三氯乙酸(TCA)以终止反应。将板密封并在室温下再摇动120分钟，然后离心。使用 Top-Count 确定与 FlashPlate 结合的放射性信号。 PARP1 Km 使用 Michaelis-Menten 方程从不同的底物浓度 (1-100 mmol/L NAD) 中确定。根据以下公式从酶抑制曲线计算化合物Ki：Ki 1/4 IC50/[1+(底物)/Km]。 PARP2 酶和化合物 Ki 的 Km 使用相同的测定方案测定，不同之处在于在室温下反应中使用 30 ng PARP2、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 20 mmol/L 冷 NAD 30 分钟。细胞分析：BMN 673 对 11 种 SCLC 细胞系表现出有效的抑制作用（IC50=1.7 至 15 nmol/L），这些细胞系均在临床可达到的范围内。此外，对 BMN673 的敏感性与 DNA 修复蛋白表达和 PI3K 通路活性相关。

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Talazoparib (BMN 673) 能强效且选择性地抑制PARP1和PARP2的酶活性，其效力优于veliparib、rucaparib和olaparib。[1]
在LoVo细胞的实验中，Talazoparib (BMN 673) 抑制过氧化氢诱导的聚（ADP-核糖）（PAR）形成，EC50为2.5 nM，证明了其细胞内PARP抑制能力。[1]
Talazoparib (BMN 673) 对同源重组（HR）介导的DNA双链断裂修复（DSBR）存在缺陷的肿瘤细胞系（如携带BRCA1、BRCA2或PTEN突变的细胞）表现出选择性细胞毒性。例如，在BRCA1突变细胞系SUM149中，半数生存分数（SF50）为8.57 x 10^-6 M，其效力比veliparib强超过10^5倍。[1]
在BRCA2缺陷的Capan-1细胞中，Talazoparib (BMN 673) 单药细胞毒性实验的IC50为5 nM。[1]
在CAL51细胞中进行的不偏向性siRNA筛选发现，沉默参与HR/DSBR的基因（如BRCA1、BRCA2、PALB2、ATM、ATR）能显著增强细胞对Talazoparib (BMN 673)的敏感性，证实了其与HR缺陷的合成致死作用机制。[1]
Talazoparib (BMN 673) 在低至100 pM的浓度下即可诱导DNA损伤生物标志物（如核内γH2AX焦点）的形成。[1]
Talazoparib (BMN 673) 在体外能增强DNA损伤剂（如替莫唑胺和SN-38（伊立替康的活性代谢物））的细胞毒性作用。在LoVo细胞中，与200 µM替莫唑胺联用时，Talazoparib (BMN 673)的GI50为3 nM。[1]
针对一组受体、离子通道和酶（包括PARG和hERG钾离子通道）的特异性筛选表明，在10 µM浓度下，Talazoparib (BMN 673) 未显示出显著的脱靶相互作用。在浓度高达100 µM时也未观察到显著的hERG抑制。[1]

在大鼠药代动力学研究中，BMN 673 显示出 >50% 的口服生物利用度和药代动力学特性，可实现每日单次给药。在 MX-1 异种移植肿瘤模型研究中，每日口服 BMN 673 可以剂量依赖性方式显着增强细胞毒性疗法的抗肿瘤作用。

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口服单药Talazoparib (BMN 673) 在携带BRCA1或PTEN缺陷的小鼠异种移植瘤模型中显示出显著的抗肿瘤活性。[1]
在携带BRCA1缺陷的MX-1肿瘤异种移植瘤的小鼠中，每日一次（QD）口服0.33 mg/kg剂量的Talazoparib (BMN 673)，持续28天，可显著抑制肿瘤生长，6只小鼠中有4只达到完全缓解（肿瘤无法触及）。0.1 mg/kg的较低剂量也显示出活性。[1]
在MX-1模型中，每日两次（BID）给药Talazoparib (BMN 673)（0.165 mg/kg/次），持续28天，比每日一次给药（0.33 mg/kg/次）更有效，导致6只小鼠全部达到完全缓解，且在治疗停止后8周内无肿瘤再生。[1]
口服Talazoparib (BMN 673) 也能抑制PTEN缺失的异种移植瘤（MDA-MB-468和LNCaP）的生长。[1]
在MX-1异种移植瘤模型中，Talazoparib (BMN 673) 以剂量依赖的方式增强了顺铂和卡铂的抗肿瘤效果。[1]
在携带MX-1肿瘤的小鼠中，单次口服Talazoparib (BMN 673)（1 mg/kg）可在给药后2小时和8小时大幅降低瘤内PAR水平（PARP抑制的生物标志物），并在24小时部分恢复。[1]

为了确定 PARP 抑制剂 Ki，在 96 孔 FlashPlate 中使用 0.5 U PARP1 酶、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 5 mmol/L 冷 NAD (Sigma) 在最终样品中进行酶测定。 50 mL 反应缓冲液，含有 10% 甘油 (v/v)、25 mmol/L HEPES、12.5 mmol/L MgCl2、50 mmol/L KCl、1 mmol/L 二硫苏糖醇 (DTT) 和 0.01% NP-40 (v/v)，pH 7.6。将 NAD 添加到 PARP 反应混合物中（无论有或没有抑制剂）以启动反应，然后在室温下孵育一分钟。然后通过向每个孔中添加50微升冰冷的20%三氯乙酸(TCA)来终止反应。将板密封并在室温下另外摇动120分钟后，进行离心。 Top-Count 用于确定与 FlashPlate 结合的放射性信号。采用 Michaelis-Menten 方程计算不同底物浓度（1 至 100 mmol/L NAD）下的 PARP1 Km。使用公式 Ki 1/4 IC50/[1+（底物）/Km]，从酶抑制曲线计算化合物 Ki。使用相同的测定方案，发现了 PARP2 酶的 Km 和化合物 Ki。然而，反应在室温下运行 30 分钟，而不是使用 30 ng PARP2、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 20 mmol/L 冷 NAD。

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PARP酶测定[1]
根据制造商的说明，使用Trevigen的PARP检测试剂盒评估测试化合物抑制PARP-1酶活性的能力。采用GraphPad Prism5软件计算IC50值。对于PARP抑制剂Ki的测定，酶分析在96孔FlashPlate上进行，0.5单位PARP1酶，0.25倍活化DNA， 0.2 μCi [3H] NAD和5 μM冷NAD，最终体积为50 μL反应缓冲液，含10%甘油（v/v）， 25 mM Hepes, 12.5 mM MgCl2, 50 mM KCl， 1 mM DTT和0.01% NP-40(v/v), pH 7.6。将NAD加入到有或没有抑制剂的PARP反应混合物中，在室温下孵育1分钟，开始反应。然后在每孔中加入50 μL冰凉的20% TCA以停止反应。将板密封并在RT下振荡120分钟，然后离心。使用TopCount测定绑定到FlashPlate的放射性信号。采用Michaelis-Menten方程测定不同底物浓度（1-100 μM NAD）下PARP1 Km。根据酶抑制曲线计算化合物Ki，公式为：Ki = IC50/（1+[底物]/Km）。除30 ng PARP2、0.25x活化DNA、0.2 μCi [3H] NAD和20 μM冷NAD在室温下反应30min外，采用相同的检测方法测定PARP2酶Km和化合物Ki。

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Biacore结合试验[1]
我们自制了带有n端6xhis标签的重组人PARP1 （rhPARP1）催化结构域（残基662 - 1011），并使用Biacore T200 （GE Healthcare）进行PARP抑制剂相互作用的结合试验。通过胺偶联法将rhPARP1固定在CM5传感器芯片上。简单地说，首先以10 μL/min的速率注射新鲜制备的50 mM NHS: 200 mM EDC(1:1)，以10 μL/min的速度注射7 min，激活CM5芯片的一个流动细胞。然后以10 μL/min的速度将rhPARP1 （100 μg/mL, 10 mM MES pH 6.5）注射到流式细胞上60秒。以10 μL/min注射1M乙醇胺7 min阻断剩余活性偶联位点。固定化缓冲液含有10 mM Hepes pH 7.4, 150 mM NaCl， 0.05%表面活性剂P20, 5 mM MgCl2和0.5 mM TCEP（三（2-羧乙基）膦）。固定水平为~7600 RU。为了测量结合动力学，在芯片表面注射浓度增加的PARP抑制剂（12.5、25、50、100、200 nM），每次注射60秒。最后一次注射后，在运行缓冲液（固定缓冲液+ 1% DMSO）中进行3600秒的解离期。流速为50 μL/min。根据参考流的信号对传感器图进行校正后，使用Biacore T200评估软件ver.1.0计算动力学。

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细胞内PAR形成试验[1]
细胞PAR合成试验评估了测试化合物抑制PAR聚合的能力。在96孔微滴板中生长的LoVo人结直肠肿瘤细胞在增加PARP抑制剂浓度的条件下预处理30分钟，然后加入终浓度为50 mM的H2O2。在室温下处理5分钟后，细胞在- 20°C下用预冷甲醇/丙酮（7:3）固定10分钟。固定细胞用抗par单克隆抗体孵育60 min，然后用FITC偶联山羊抗小鼠IgG（稀释1:100）和1 μg/mL DAPI孵育60 min，用DAPI信号归一化FITC信号，用GraphPad Prism计算EC50值。

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使用标准的PARP检测试剂盒评估化合物对PARP1酶的抑制活性。反应体系通常包含PARP1酶、激活的DNA、适当缓冲液中的标记与非标记NAD+混合物。通过加入NAD+启动反应，在室温下短暂孵育，然后用三氯乙酸（TCA）终止。通过测量放射性信号的掺入来确定酶活性。根据抑制曲线计算IC50值。对于Ki的测定，在类似的条件下于专用板中进行实验，并根据测定的NAD+ Km值，使用Cheng-Prusoff方程计算Ki。[1]
使用表面等离子共振（SPR）技术测定Talazoparib (BMN 673) 与重组人PARP1催化结构域的结合动力学。将PARP1蛋白固定于传感器芯片上。将浓度递增的抑制剂溶液注入流过芯片表面，实时监测结合和解离过程。通过分析传感图计算结合速率（kon）、解离速率（koff）和平衡解离常数（KD）。[1]

对十一种 SCLC 细胞系，BMN 673 具有很强的抑制作用（IC50=1.7 至 15 nmol/L），所有这些都在临床可行的范围内。此外，DNA 修复蛋白的表达与 PI3K 通路的活性以及对 BMN673 的敏感性之间存在相关性。

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共焦显微镜[1]
细胞接种于6孔板盖盖上，24小时后用不同浓度的奥拉帕尼或Talazoparib (BMN 673; MDV3800) 处理24小时后，将细胞用10%福尔马林（3.7% PFA）固定1小时。用0.2% Triton X-100在PBS中渗透20分钟，用50 μL DNase I（在PBS中稀释1/10）在37℃下处理1小时，然后用IFF （PBS + 1% BSA和2% FBS，过滤灭菌）阻断1小时。盖片与兔抗γ - h2ax原代和小鼠抗rad51原代（均为1:1000,50μL IFF）在4°C下孵育过夜。次日，细胞与抗小鼠Alexafluor 546和抗兔Alexafluor 488（均为1:1000,50μL IFF）共孵育1小时。细胞在含DAPI 1:10.000的PBS中洗涤10分钟，用vectasshield和指甲油贴在玻璃板上。使用徕卡共聚焦显微镜对每个盖盖至少拍摄四张照片，随后对细胞进行计数。每次覆盖至少评估100个细胞，如果每个细胞核有超过5个病灶，则为γ - h2ax阳性。绘制阳性细胞的百分比。

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通过测量细胞内PAR形成来评估细胞PARP抑制。将生长在微孔板中的LoVo细胞用PARP抑制剂预处理，然后暴露于过氧化氢以诱导DNA损伤和PAR合成。固定、透化细胞，用抗PAR抗体染色，再用荧光二抗染色。将荧光信号与核染色（DAPI）信号标准化，用于确定产生50%抑制所需的浓度（EC50）。[1]
对于siRNA筛选，将CAL51细胞与靶向960个基因的siRNA文库进行反向转染。48小时后，用各PARP抑制剂在其相应的SF80浓度或溶剂对照处理细胞。5天后，使用基于ATP发光的检测法评估细胞活力。计算药物效应（DE）Z分数，以鉴定使细胞对药物敏感化的siRNA。[1]
使用长期（10-12天）细胞生长抑制实验在96孔板中评估单药细胞毒性。用浓度递增的PARP抑制剂处理细胞，定期更换培养基和化合物。使用基于ATP发光的检测法测定细胞存活率，并计算IC50/GI50值。[1]
进行克隆形成实验以评估长期的细胞生殖性死亡。将细胞以低密度接种于多孔板中，用PARP抑制剂处理14天（定期更换培养基），然后固定并染色。计数克隆数，并计算相对于溶剂对照组的存活分数。[1]
通过将细胞与固定浓度的细胞毒剂（如替莫唑胺）和浓度递增的PARP抑制剂共同处理5天来进行化学增敏实验。测定细胞存活率，并确定联合用药的GI50值。[1]
通过γH2AX焦点的免疫荧光染色评估DNA损伤反应。将生长在盖玻片上的细胞用抑制剂处理、固定、透化，并用抗γH2AX抗体和荧光二抗染色。复染细胞核。使用共聚焦显微镜定量每个细胞核中具有超过5个γH2AX焦点的细胞百分比。[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. Xenograft experiments[1]
Female 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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PAR assay in vivo[1]
MX-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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Female 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]
For 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]
For 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]
For 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
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. Steady state was reached within two to three weeks of therapy. The Tmax ranges from one to two hours. 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.
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.
The mean apparent volume of distribution of talazoparib is 420 L.
The mean apparent oral clearance is 6.45 L/h. The inter-subject variability is 31%.

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Metabolism / Metabolites
Talazoparib undergoes minimal hepatic metabolism. The metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro talazoparib, and glucuronide conjugation.

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Biological Half-Life
The mean terminal plasma half-life (±standard deviation) is 90 (±58) hours in patients with cancer.

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In vitro metabolism studies in liver microsomes from rats, dogs, and humans showed that Talazoparib (BMN 673) had excellent metabolic stability, with more than 90% of the parent compound remaining after 2 hours of incubation at 1 µM concentration. [1]
In rat pharmacokinetic studies, oral administration of Talazoparib (BMN 673) formulated in 0.5% carboxylmethyl cellulose resulted in an absolute oral bioavailability of greater than 40%. [1]
The pharmacokinetic properties predicted a human half-life sufficient to support once-daily dosing. [1]
In vitro studies showed that at concentrations up to 10 µM, Talazoparib (BMN 673) did not inhibit the major human hepatic cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4). [1]

Hepatotoxicity
Elevations in serum aminotransferase levels are common during talazoparib therapy occurring in 33% of patients, but rising above 5 times the upper limit of the normal range in only 1%. The elevations are generally transient and not associated with symptoms or jaundice. Furthermore, similar rates of aminotransferase elevations were reported in control, comparator arms. Talazoparib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with using talazoparib and other PARP inhibitors, their potential for causing liver injury is not well defined.
Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of talazoparib during breastfeeding. Because talazoparib is 74% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during talazoparib therapy and for one month after the last dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
_In vitro_, the protein binding of talazoparib is 74% and is independent of talazoparib concentration.

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In vitro assessment of the human Ether-à-go-go-Related Gene (hERG) potassium channel showed no significant inhibition by Talazoparib (BMN 673) at concentrations as high as 100 µM, suggesting a low risk of causing clinical cardiac QTc prolongation. [1]
In vivo, single-agent oral administration of Talazoparib (BMN 673) at doses up to 0.33 mg/kg/day for 28 days was generally well-tolerated in mice, with no animal lethality or significant body weight loss observed. [1]
Combination of Talazoparib (BMN 673) with cisplatin resulted in moderate, dose-dependent body weight loss in mice (maximum average loss of 11% at 1 mg/kg BMN 673 + cisplatin), with one animal death at the highest combination dose. Animals treated with cisplatin alone had a maximum average weight loss of 3%. [1]
Combination with carboplatin did not cause significant body weight loss or animal lethality under the tested conditions. [1]

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

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

Talazoparib is an orally available small molecule inhibitor of the DNA repair enzyme poly ADP-ribose polymerase (PARP) which is used as an antineoplastic agent in the treatment of selected cases of breast cancer. Talazoparib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.
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. Developed by Pfizer, talazoparib was first approved by the FDA in October 2018 and by the EMA in June 2019. It was approved by Health Canada in September 2020. Talazoparib is currently used in the treatment of BRCA-mutated breast cancer and HRR-mutated prostate cancer.
Talazoparib is a Poly(ADP-Ribose) Polymerase Inhibitor. The mechanism of action of talazoparib is as a Poly(ADP-Ribose) Polymerase Inhibitor.
Talazoparib is an orally available small molecule inhibitor of the DNA repair enzyme poly ADP-ribose polymerase (PARP) which is used as an antineoplastic agent in the treatment of selected cases of breast cancer. Talazoparib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.
Talazoparib is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity. Talazoparib 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. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks.
See also: Talazoparib Tosylate (active moiety of).

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Drug 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. In the US, talazoparib is also indicated in combination with [enzalutamide] for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
Talzenna is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2 mutations, who have HER2-negative locally advanced or metastatic breast cancer . Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy.
Treatment of Ewing sarcoma
Treatment of breast malignant neoplasms, Treatment of prostate malignant neoplasms

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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_. Talazoparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2. _In vitro_, talazoparib binds to PARP-1 and -2 isoforms with similar affinity. 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. 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. By inhibiting PARP, talazoparib increases the formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.

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Talazoparib (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]phthalazin-3(7H)-one. [1]
The anti-tumor activity of PARP inhibitors like Talazoparib (BMN 673) is based on the concept of synthetic lethality, selectively killing cancer cells with pre-existing defects in DNA repair pathways, particularly homologous recombination (e.g., due to BRCA1/2 mutations). [1]
At the time of publication, Talazoparib (BMN 673) was in early-phase clinical development, with ongoing Phase I trials assessing its safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with advanced solid tumors or hematological malignancies and DNA repair deficiencies. [1]
The favorable metabolic stability, oral bioavailability, and potency profile of Talazoparib (BMN 673) suggested it as a promising addition to the class of PARP inhibitors. [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

91.98

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.57 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.57 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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