N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with α-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through α-folate receptor (α-FR) transport. The α-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2′-deoxyuridine-5′-monophosphate, and a model for a similar complex with human TS.

中文翻译：

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N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-四氢-2-(羟甲基)-4-oxo-3H-cyclopenta[g]]的开发和结合模式评估quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic Acid (BGC 945)，一种靶向肿瘤细胞的新型胸苷酸合成酶抑制剂

N -[4-[2-Propyn-1-yl[(6 S )-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3 H - cyclopenta[ g ]quinazolin-6-基]氨基]苯甲酰基] -升-γ谷氨酰基- d -谷氨酸1（BGC 945，现在称为 ONX 0801），是在伦敦癌症研究所发现的一种小分子胸苷酸合成酶 (TS) 抑制剂。它已获得 Onyx Pharmaceuticals 的许可，并处于 1 期临床研究中。它是一种类似于 TS 抑制剂普维曲塞和雷替曲塞的新型抗叶酸药物，将胸苷酸合酶的酶促抑制与 α-叶酸受体介导的肿瘤细胞靶向相结合。因此，由于通过 α-叶酸受体 (α-FR) 转运的选择性细胞内积累，它具有低毒性的功效潜力。α-FR 是一种细胞表面受体糖蛋白，主要在卵巢癌和肺癌肿瘤中过度表达，对其1的亲和力与其天然配体叶酸的亲和力相似。本研究描述了1，其与大肠杆菌TS 和 2'-脱氧尿苷-5'-单磷酸酯复合物的 X 射线晶体结构，以及与人类 TS 类似复合物的模型。