PARP1 ( IC50 = 0.57 nM )
In vitro activity: Talazoparib is a strong inhibitor of PARP1/2 (PARP1 IC50=0.57 nM); at concentrations up to 1 μM, it has no effect on PARG activity. With a dissociation constant (K_D) of 0.29 nM, talazoparib binds to PARP1. With K_is values of 1.20 and 0.85 nM, respectively, talazoparib inhibits PARP1 and -2 to a comparable degree. With 20–200 times more potency than current PARP1/2 inhibitors, talazoparib specifically targets tumor cells with BRCA1, BRCA2, or PTEN gene defects. The drug talazoparib targets tumor cells that have defects in homologous recombination genes. Both BRCA1-deficient tumor models (MX-1 and SUM149) and BRCA2-deficient tumor models (Capan-1) exhibit significant sensitivity to talazoparib. At concentrations as low as 100 pM, talazoparib induces nuclear γ-H2AX foci[1].

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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在生物化学酶活性测定中，他拉唑帕尼托西酸盐抑制PARP1的IC50为0.57 nM，效力强于维利帕尼、鲁卡帕尼和奥拉帕尼。[1]
在LoVo细胞中测量抑制过氧化氢诱导的聚ADP核糖合成的细胞实验中，他拉唑帕尼托西酸盐的EC50为2.5 nM。[1]
他拉唑帕尼托西酸盐选择性杀死具有同源重组缺陷的肿瘤细胞。在BRCA2缺陷的胰腺癌细胞系Capan-1中，其单药细胞毒性IC50为5 nM。[1]
在一组人类肿瘤细胞系的集落形成或2D细胞毒性实验中，他拉唑帕尼托西酸盐在BRCA1缺陷、BRCA2缺陷和PTEN缺陷模型中显示出显著效力，而在HR功能正常的模型中效力较低。与其他PARP抑制剂相比，其在BRCA缺陷与正常细胞之间的治疗窗口更大。[1]
在BRCA缺陷的同基因模型（具有BRCA1缺陷的小鼠ES细胞和具有BRCA2敲除的人DLD1细胞）中，他拉唑帕尼托西酸盐在比维利帕尼、鲁卡帕尼或奥拉帕尼低得多的浓度下选择性抑制BRCA缺陷细胞的生长。[1]
在CAL51细胞中使用靶向960个基因的siRNA库进行的平行RNA干扰筛选表明，对他拉唑帕尼托西酸盐最显著的增敏作用是由靶向HR/双链断裂修复相关基因的siRNA引起的。其遗传增敏谱与其他PARP抑制剂无显著差异。[1]
他拉唑帕尼托西酸盐在低浓度下诱导DNA损伤生物标志物。它在低至100 pM的浓度下即可诱导细胞核γH2AX灶形成。[1]
他拉唑帕尼托西酸盐增强了DNA损伤剂的细胞毒性。与替莫唑胺联用时，在LoVo细胞中达到50%生长抑制的GI50为3 nM。它还在体外以剂量依赖性方式增强SN-38的效果，并与铂类药物显示出相加作用。[1]
他拉唑帕尼托西酸盐在高达1 μM的浓度下不抑制PARG活性。在10 μM浓度下进行的广泛脱靶筛选未显示显著相互作用。在高达100 μM的浓度下，对hERG钾通道无显著抑制。[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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在携带BRCA1缺陷的MX-1人乳腺肿瘤异种移植物的裸鼠中，每天一次口服他拉唑帕尼托西酸盐0.33 mg/kg，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。0.1 mg/kg的较低剂量效果较小，但仍比每天一次口服100 mg/kg奥拉帕尼更有效。[1]
在携带MX-1异种移植物的鼠中单次口服他拉唑帕尼托西酸盐可显著降低给药后2小时和8小时的瘤内PAR水平，24小时后部分恢复。[1]
在MX-1模型中，每天两次给药方案比每天一次给药方案更有效，可防止肿瘤在治疗结束后重新生长。[1]
他拉唑帕尼托西酸盐在PTEN缺失的异种移植模型中也显示出抗肿瘤活性，导致显著的肿瘤生长延迟。[1]
他拉唑帕尼托西酸盐增强了顺铂和卡铂在MX-1异种移植模型中的抗肿瘤效果。与顺铂联用显示剂量依赖性增敏作用。[1]

酶测定在 96 孔 FlashPlates 中进行，最终体积为 50 mL 反应缓冲液，其中含有 0.5 U PARP1 酶、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 5 mmol/L 冷 NAD (Sigma)，其中含有 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。将含有或不含抑制剂的 NAD 添加到 PARP 反应混合物中以启动反应，然后将其在室温下静置一分钟。为了停止反应，随后将 50 微升冰冷的 20% 三氯乙酸 (TCA) 添加到每个孔中。将板密封并在室温下另外摇动 120 分钟后进行离心。 Top-Count 用于识别与 FlashPlate 结合的放射性信号。使用 Michaelis-Menten 方程，计算一系列底物浓度 (1-100 mmol/L NAD) 的 PARP1 Km。利用公式 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测定 PARP2 酶 Km 和化合物 Ki，不同之处在于在反应 30 小时期间使用 30 ng PARP2、0.25x 活化 DNA、0.2 mCi [3H] NAD 和 20 mmol/L 冷 NAD。分钟的室温持续时间。

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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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PARP酶抑制实验：使用商业PARP检测试剂盒评估测试化合物抑制PARP1酶活性的能力。反应体系包含PARP1酶、活化DNA、NAD和测试化合物。孵育后，用三氯乙酸终止反应，通过闪烁计数测定结合到板上的放射性信号，并根据剂量反应曲线计算IC50。通过变化NAD浓度确定Km，并使用公式Ki = IC50/(1+[底物]/Km)计算Ki。使用PARP2酶的类似方案用于测定PARP2 Ki。[1]
Biacore结合实验： 通过胺偶联法将重组人PARP1催化结构域固定在CMS传感器芯片上。以递增浓度的测试化合物注入芯片表面，每次注入60秒，然后在运行缓冲液中进行长时间解离。使用参考流动池校正传感图，并使用评估软件计算结合动力学参数和离解常数。[1]

为期五天，替莫唑胺 (TMZ) 和他拉佐帕尼 (10, 40 nM) 单独或联合给予 LoVo 细胞。 CellTiter-Glo 测定用于确定存活率。 [1] 一组 11 个 SCLC 细胞系（IC50=1.7 至 15 nmol/L），所有这些细胞系都在临床可行的范围内，证明了 BMN 673 的强大抑制作用。此外，PI3K 通路活性和 DNA 修复蛋白表达与 Talazoparib (BMN 673; MDV3800)  敏感性相关。

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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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细胞内PAR形成实验： 将生长在96孔板中的LoVo人结直肠肿瘤细胞用PARP抑制剂预处理30分钟。然后通过添加过氧化氢诱导PAR合成5分钟。固定细胞后，使用抗PAR单克隆抗体和一抗FITC偶联的二抗进行免疫荧光染色，并用DAPI复染。将FITC信号归一化为DAPI信号，并根据剂量反应曲线计算EC50。[1]
集落形成生存实验：将细胞以低密度接种于6孔板中。24小时后，更换为含PARP抑制剂的新鲜培养基。每周更换两次含抑制剂的培养基，持续14天。然后用三氯乙酸固定菌落，用磺基罗丹明B染色，计数，并归一化至载体处理对照组以计算生存分数。[1]
单药细胞毒性和化学增敏实验：对于单药细胞毒性，将细胞接种于96孔板，用递增浓度的PARP抑制剂处理10-12天。使用发光细胞活力测定法测定细胞存活率。对于化学增敏实验，将不同浓度的PARP抑制剂与固定浓度的细胞毒剂组合处理细胞5天，然后测定细胞活力。[1]
siRNA筛选：将CAL51细胞接种于96孔板，用靶向960个基因的siRNA库转染。转染后48小时，用各PARP抑制剂在其SF80浓度或载体处理细胞5天。使用发光法评估细胞活力。分析数据以计算每个siRNA的药物效应Z分数，识别其沉默能增敏细胞对药物反应的基因。[1]
γH2AX灶免疫荧光： 将接种在盖玻片上的细胞用PARP抑制剂处理24小时，固定、透化并用DNase I处理。封闭后，与抗γH2AX和抗RAD51的一抗在4°C孵育过夜。然后与荧光染料偶联的二抗和DAPI孵育。通过共聚焦显微镜获取图像。计数每个细胞核中超过5个γH2AX灶的细胞为阳性细胞。[1]

Mice: In single-agent trials, oral gavage (per os) is used to deliver olaparib (100 mg/kg), Talazoparib (0.33 or 0.1 mg/kg/d), or vehicle (10% DMAc, 6% Solutol, and 84% PBS) once daily or twice daily, respectively, for a total of 28 days. After the final dosage day, mice are observed every day for an additional 10 days[1]. 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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Single-Agent Efficacy in Xenograft Models: Female athymic nu/nu mice (8-10 weeks old) were implanted subcutaneously with tumor cells (e.g., LNcap, MDA-MB-468) or tumor fragments (MX-1). When tumors reached an average volume of ~150 mm³, mice were randomized into treatment groups. Talazoparib tosylate (BMN 673) was administered orally by gavage (p.o.) at specified doses (e.g., 0.1, 0.33 mg/kg) once daily (QD) or twice daily (BID, e.g., 0.165 mg/kg/dose) for 28 consecutive days. Olaparib (100 mg/kg, p.o., QD) or vehicle (10% DMAc, 6% Solutol, 84% PBS) served as controls. Tumor volumes were measured twice weekly. [1]
Pharmacodynamic (PAR Inhibition) Study in Xenografts:Mice bearing MX-1 xenografts received a single oral dose of Talazoparib tosylate (1 mg/kg), olaparib (100 mg/kg), or vehicle. 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 commercial ELISA kit. [1]
Combination Therapy with DNA-Damaging Agents:For combination with cisplatin, Talazoparib tosylate or vehicle was administered p.o. once daily for 8 days starting on day 1. Cisplatin (6 mg/kg) or saline vehicle was administered intraperitoneally (i.p.) as a single injection on day 3, 30 minutes after the PARP inhibitor. For combination with carboplatin, a similar schedule was used where Talazoparib tosylate was given p.o. once daily for 5 or 8 days and carboplatin (35 mg/kg, single i.p. dose) was administered 30 minutes after the PARP inhibitor on day 3. Tumor growth and animal body weight were monitored. [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 tosylate had excellent metabolic stability, with >90% of the compound remaining after 2 hours of incubation at 1 μM concentration. [1]
In rat pharmacokinetic studies, Talazoparib tosylate demonstrated an absolute oral bioavailability of >40% when dosed in 0.5% carboxylmethyl cellulose. [1]
Talazoparib tosylate (at concentrations up to 10 μM) did not inhibit the five 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 the MX-1 xenograft model, oral administration of Talazoparib tosylate at 0.33 mg/kg and 0.1 mg/kg once daily for 28 days was well tolerated, with no animal lethality or significant body weight loss observed. [1]
In the combination study with cisplatin, treatment regimens involving Talazoparib tosylate plus cisplatin resulted in moderate, dose-dependent body weight loss. Maximum average weight losses were 11%, 6%, 5%, and 3% for groups receiving Talazoparib tosylate at 1, 0.33, 0.1, and 0.033 mg/kg plus cisplatin, respectively (compared to 3% for cisplatin alone). One animal died in the 1 mg/kg Talazoparib tosylate plus cisplatin group on Day 20. Most animals recovered body weight after treatment ended. [1]
In the MX-1 model with twice-daily dosing (0.165 mg/kg/dose, BIDx28), one out of six mice had significant weight loss (>20%) and was sacrificed on day 53. All other animals in that study tolerated the treatment well. [1]
No significant inhibition of the hERG potassium channel was observed in vitro at concentrations up to 100 μM, suggesting a low risk for clinical cardiac QTc prolongation. [1]

[1]. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013 Sep 15;19(18):5003-15.

Talazoparib Tosylate is the tosylate salt form of talazoparib, an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity. Upon administration, 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 (has active moiety).

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Drug Indication
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.

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\n\nTalazoparib 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.\n

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Talazoparib tosylate (BMN 673) is a novel, highly potent, and selective inhibitor of PARP1 and PARP2, designed to have favorable metabolic stability, oral bioavailability, and pharmacokinetic properties. [1]
The drug exploits the concept of synthetic lethality, selectively killing cancer cells with defects in homologous recombination DNA repair, such as those with BRCA1, BRCA2, or PTEN mutations. [1]
Its chemical name 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. It is one of the trans isomers (LT-00673) derived from the racemate LT-00628. The other trans isomer (LT-00674) and the cis isomers were much less active. [1]
The potent anti-tumor activity of Talazoparib tosylate is strongly correlated with its PARP inhibitory activity, as evidenced by chiral selectivity studies comparing it with its less active isomer. [1]
The drug was in early-phase clinical development at the time of publication, with ongoing Phase I trials in patients with advanced tumors harboring DNA-repair pathway deficiencies and in patients with advanced hematological malignancies. [1]

C26H22F2N6O4S

552.56

552.139

C, 56.52; H, 4.01; F, 6.88; N, 15.21; O, 11.58; S, 5.80

1373431-65-2

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

135565654

White to off-white solid powder

4.22

154.73

3

10

3

39

861

2

S(C1C=CC(C)=CC=1)(=O)(=O)O.FC1C=C2C(NN=C3C2=C(C=1)N[C@H](C1C=CC(=CC=1)F)[C@H]3C1=NC=NN1C)=O

QUQKKHBYEFLEHK-QNBGGDODSA-N

InChI=1S/C19H14F2N6O.C7H8O3S/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;1-6-2-4-7(5-3-6)11(8,9)10/h2-8,15-16,24H,1H3,(H,26,28);2-5H,1H3,(H,8,9,10)/t15-,16-;/m1./s1

(11S,12R)-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;4-methylbenzenesulfonic acid

BMN 673 tosylate; BMN673; BMN-673; UNII-02WK9U5NZC; 02WK9U5NZC; Talazoparib tosylate [USAN]; LT673 tosylate; LT 673; LT-673 tosylate; MDV-3800 tosylate; MDV 3800; MDV3800 tosylate; 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

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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 (4.52 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 (4.52 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 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 5%DMSO+ 40%PEG300+ 5%Tween 80+ 50%ddH2O: 2.5mg/ml (6.57mM)

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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));
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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；
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