Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas

Vaswani Rishi G.; Gehling Victor S.; Dakin Les A.; Cook Andrew S.; Nasveschuk Christopher G.; Duplessis Martin; Iyer Priyadarshini; Balasubramanian Srividya; Zhao Feng; Good Andrew C.; Campbell Robert; Lee Christina; Cantone Nico; Cummings Richard T.; Normant Emmanuel; Bellon Steven F.; Albrecht Brian K.; Harmange Jean-Christophe; Trojer Patrick; Audia James E.; Zhang Ying; Justin Neil; Chen Shuyang; Wilson Jon R.; Gamblin Steven J.

首页> 外文期刊>Journal of Medicinal Chemistry >Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas

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Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas

机译：（R）-N-（（4-甲氧基-6-甲基-2-氧代-1,2，-二氢吡啶基-3-基）甲基）-2-甲基-1-（1-（1-（2， 2,2-三氟乙基）哌啶-4-基）乙基）-1H-吲哚-3-羧酰胺（CPI-1205）是组蛋白甲基转移酶EZH2的强效和选择性抑制剂，适用于B细胞淋巴瘤的I期临床试验

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Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 mu M, cellular EC50 = 0.032 mu M) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.

机译：聚梳抑制复合物2（PRC2）已显示在转录沉默中起主要作用，部分原因是在组蛋白3的赖氨酸27上安装了甲基化标记。PRC2功能失调与某些恶性肿瘤和不良预后相关。 EZH2是PRC2复合物的催化引擎，因此代表了药理学干预的主要候选肿瘤学靶标。在这里，我们报告了我们基于吲哚的EZH2抑制剂系列的优化，该系列可鉴定CPI-1205，高效（生化IC50 = 0.002μM，细胞EC50 = 0.032μM）和EZH2选择性抑制剂。当以160 mg / kg BID剂量给药时，该化合物在Karpas-422异种移植模型中显示出强大的抗肿瘤作用，目前处于I期临床试验中。另外，我们公开了与人PRC2复合物结合的抑制剂系列的共晶体结构。

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《Journal of Medicinal Chemistry》 |2016年第21期|共14页
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Vaswani Rishi G.; Gehling Victor S.; Dakin Les A.; Cook Andrew S.; Nasveschuk Christopher G.; Duplessis Martin; Iyer Priyadarshini; Balasubramanian Srividya; Zhao Feng; Good Andrew C.; Campbell Robert; Lee Christina; Cantone Nico; Cummings Richard T.; Normant Emmanuel; Bellon Steven F.; Albrecht Brian K.; Harmange Jean-Christophe; Trojer Patrick; Audia James E.; Zhang Ying; Justin Neil; Chen Shuyang; Wilson Jon R.; Gamblin Steven J.;
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1. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas [J] . Vaswani Rishi G., Gehling Victor S., Dakin Les A., Journal of Medicinal Chemistry . 2016,第21期

机译：（R）-N-（（4-甲氧基-6-甲基-2-氧代-1,2，-二氢吡啶基-3-基）甲基）-2-甲基-1-（1-（1-（2， 2,2-三氟乙基）哌啶-4-基）乙基）-1H-吲哚-3-羧酰胺（CPI-1205）是组蛋白甲基转移酶EZH2的强效和选择性抑制剂，适用于B细胞淋巴瘤的I期临床试验
2. Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5- yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine [J] . AnnediS.C., MaddafordS.P., RamnauthJ., European Journal of Medicinal Chemistry: Chimie Therapeutique . 2012,第Null期

机译：发现一种有效的，口服生物利用度和高选择性的人类神经元一氧化氮合酶（nNOS）抑制剂N-（1-（1-哌啶丁-4-基）吲哚满-5-基）噻吩-2-羧酰亚胺作为临床前开发候选药物用于治疗偏头痛
3. Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5- yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine [J] . AnnediS.C., MaddafordS.P., RamnauthJ., European Journal of Medicinal Chemistry: Chimie Therapeutique . 2012,第Null期

机译：发现有效，口服生物的生物和高选择性的人神经元一氧化氮合酶（NNO）抑制剂，N-（1-（哌啶-4-基）吲哚啉-5-基）噻吩-2-羧酰胺酰胺酰胺作为临床前发育候选者用于治疗偏头痛
4. Identificationof (R)-N-((4-Methoxy-6-methyl-2-oxo-12-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(222-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205) a Potent and SelectiveInhibitor of Histone Methyltransferase EZH2 Suitable for Phase IClinical Trials for B-Cell Lymphomas [O] . Rishi G. Vaswani, *, δ, -1

机译：身份证明（R）-N-（（（4-Methoxy-6-methyl-2-oxo-12-dihydropyridin-3-yl）methyl）-2-甲基-1-（1-（1-（22 2-三氟乙基）哌啶-4-基）乙基）-1H-吲哚-3-羧酰胺（CPI-1205）有选择性组蛋白甲基转移酶EZH2的抑制剂适用于I期B细胞淋巴瘤的临床试验
5. Identification of (R)N((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)1Hindole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for BCell Lymphomas [O] . -1

机译：鉴定（r）n（（4-甲氧基-6-甲基-2-氧代-1,2-二氢吡啶-3-基-3-基）甲基）-2-甲基-1-（1-（1-（2,2， 2-三氟乙基）哌啶-4-基）乙基）1HINDOLE-3-甲酰胺（CPI-1205），效率和选择性抑制剂的组蛋白甲基转移酶EZH2，适用于BCell淋巴瘤的I相临床试验

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