We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with K_i = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC₅₀ of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC₅₀ = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.

中文翻译：

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（8 S，9 R）-5-氟-8-（4-氟苯基）-9-（1-甲基-1 H -1,2,4-三唑-5-基）-2,7的发现和表征，8,9-tetrahydro-3 H -pyrido [4,3,2-de] phthalazin-3-one（BMN 673，Talazoparib），一种新型的，高效的，口服有效的聚（ADP-核糖）聚合酶-1 / 2抑制剂，作为抗癌剂

我们发现并开发了一系列新的四氢吡啶并噻嗪酮类化合物，作为聚（ADP-核糖）聚合酶（PARP）1和2抑制剂。铅的优化导致对（8 S，9 R）-47（他拉唑帕尼; BMN 673;（8 S，9 R）-5-氟-8-（4-氟苯基）-9-（1-甲基-1）的鉴定H -1,2,4-三唑-5-基）-2,7,8,9-四氢-3 H-吡啶并[4,3,2-de]酞嗪-3-one）。该化合物的新型立体特异性双手性中心嵌入结构使它能够与PARP1 / 2蛋白进行广泛而独特的结合相互作用。（8 S，9 R）-47表现出优异的效能，分别以K _i = 1.2和0.87 nM抑制PARP1和PARP2酶的活性。它在全细胞试验中抑制PARP介导的PARylation，EC ₅₀为2.51 nM，并阻止携带突变型BRCA1 / 2的癌细胞增殖，EC ₅₀ = 0.3 nM（MX-1）和5 nM（Capan-1） ， 分别。（8 S，9 R）-47可口服，在BRCA1中显示出良好的药代动力学（PK）特性和显着的抗肿瘤功效口服MX-1突变体MX-1乳腺癌异种移植模型，以单药形式或与化疗药物（如替莫唑胺和顺铂）联用。（8 S，9 R）-47已完成1期临床试验，目前正在2期和3期临床试验中进行研究，以治疗具有种系BRCA1 / 2有害突变的局部晚期和/或转移性乳腺癌。