Development and binding mode assessment of 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 (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells.
Development and binding mode assessment of 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 (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells.
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DOI：
10.1021/jm400490e
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发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Stroud RM
中科院分区：
文献类型：
--
作者：
Tochowicz A;Dalziel S;Eidam O;O'Connell JD 3rd;Griner S;Finer-Moore JS;Stroud RM
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酸1(BGC945，现在称为ONX0801)是伦敦癌症研究所发现的一种小分子胸苷合成酶(TS)抑制剂。它获得了Onyx制药公司的许可，目前处于第一阶段临床研究。它是一种新型的抗叶酸药物，类似于TS抑制剂普列维曲塞和雷替曲塞，它结合了对胸苷合成酶的酶抑制和α-叶酸受体介导的肿瘤细胞靶向。因此，由于通过α-叶酸受体(α-FR)转运选择性地在细胞内蓄积，它具有疗效和低毒性的潜力。α-FR是一种细胞表面受体糖蛋白，主要在卵巢癌和肺癌中过度表达，其与1的亲和力与其天然配体叶酸相似。本研究描述了1的一种新的合成方法，其与大肠杆菌TS和2‘-脱氧尿苷-5’-单磷酸的配合物的X-射线晶体结构，以及与人TS类似的配合物的模型。
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 over expressed 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.
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DOI：
10.1016/b978-012369448-5.50012-4
发表时间：
2008-01-01
期刊：
CANCER DRUG DESIGN AND DISCOVERY
影响因子：
--
作者：
Jackman，Ann L.;Forster，Martin;Ng，Matthew
通讯作者：
Ng，Matthew
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444902016657
发表时间：
2002-11-01
影响因子：
2.2
作者：
Adams, PD;Grosse-Kunstleve, RW;Terwilliger, TC
通讯作者：
Terwilliger, TC
影响因子：
5.6
作者：
Laskowski, Roman A.;Swindells, Mark B.
通讯作者：
Swindells, Mark B.
影响因子：
7.3
作者：
Bavetsias, V;Marriott, JH;Jackman, AL
通讯作者：
Jackman, AL