Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

Fedoriw Andrew; Rajapurkar Satyajit R.; OBrien Shane; Gerhart Sarah V.; Mitchell Lorna H.; Adams Nicholas D.; Rioux Nathalie; Lingaraj Trupti; Ribich Scott A.; Pappalardi Melissa B.; Shah Niyant; Laraio Jenny; Liu Yan; Butticello Michael; Carpenter Chris L.; Creasy Caretha; Korenchuk Susan; McCabe Michael T.; McHugh Charles F.; Nagarajan Raman; Wagner Craig; Zappacosta Francesca; Annan Roland; Concha Nestor O.; Thomas Roberta A.; Hart Timothy K.; Smith Jesse J.; Copeland Robert A.; Moyer Mikel P.; Campbell John; Stickland Kim; Mills James; Jacques-OHagan Suzanne; Allain Christina; Johnston Danielle; Raimondi Alejandra; Scott Margaret Porter; Waters Nigel; Swinger Kerren; Boriack-Sjodin Ann; Riera Tom; Shapiro Gideon; Chesworth Richard; Prinjha Rabinder K.; Kruger Ryan G.; Barbash Olena; Mohammad Helai P.

首页> 外文期刊>Cancer Cell >Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

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Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

机译：I型PRMT抑制剂，GSK3368715的抗肿瘤活性，通过MTAP损失来协同PRMT5抑制

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Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

机译：I型蛋白质精氨酸甲基转移酶（PRMT）催化在蛋白质上的精氨酸的不对称二甲基化。 I型PRMTS及其基质涉及人类癌症，表明I型PRMTS的抑制可以提供治疗肿瘤学的治疗方法。目前的报告描述了GSK3368715（EPZ019997），一种有效的可逆型PRMT抑制剂，具有人体癌症模型中的抗肿瘤作用。当与GSK3368715结合时，PRMT5抑制PRMT5，优势II型PRMT产生协同癌细胞生长抑制。有趣的是，缺失甲硫噻吩磷酸磷酸化酶基因（MTAP）导致代谢物2-甲基噻吩醇，其内源性抑制剂的PRMT5的积累，并与细胞系中GSK3368715的敏感性相关。这些数据提供了基本原理，以探索MTAP状态作为患者选择的生物标记策略。

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《Cancer Cell》 |2019年第1期|共40页
作者
Fedoriw Andrew; Rajapurkar Satyajit R.; OBrien Shane; Gerhart Sarah V.; Mitchell Lorna H.; Adams Nicholas D.; Rioux Nathalie; Lingaraj Trupti; Ribich Scott A.; Pappalardi Melissa B.; Shah Niyant; Laraio Jenny; Liu Yan; Butticello Michael; Carpenter Chris L.; Creasy Caretha; Korenchuk Susan; McCabe Michael T.; McHugh Charles F.; Nagarajan Raman; Wagner Craig; Zappacosta Francesca; Annan Roland; Concha Nestor O.; Thomas Roberta A.; Hart Timothy K.; Smith Jesse J.; Copeland Robert A.; Moyer Mikel P.; Campbell John; Stickland Kim; Mills James; Jacques-OHagan Suzanne; Allain Christina; Johnston Danielle; Raimondi Alejandra; Scott Margaret Porter; Waters Nigel; Swinger Kerren; Boriack-Sjodin Ann; Riera Tom; Shapiro Gideon; Chesworth Richard; Prinjha Rabinder K.; Kruger Ryan G.; Barbash Olena; Mohammad Helai P.;
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GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

Epizyme Inc Cambridge MA 02139 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Med Sci &

Technol Collegeville PA 19426 USA;

GlaxoSmithKline Med Sci &

Technol Collegeville PA 19426 USA;

GlaxoSmithKline Med Sci &

Technol Collegeville PA 19426 USA;

GlaxoSmithKline Med Sci &

Technol Collegeville PA 19426 USA;

GlaxoSmithKline Med Sci &

Technol Collegeville PA 19426 USA;

GlaxoSmithKline Nonclin Safety Assessment Collegeville PA 19426 USA;

GlaxoSmithKline Nonclin Safety Assessment Collegeville PA 19426 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

Epizyme Inc Cambridge MA 02139 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

GlaxoSmithKline Epigenet Res Unit Collegeville PA 19426 USA;

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中图分类肿瘤学;
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专利

1. Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss [J] . Fedoriw Andrew, Rajapurkar Satyajit R., OBrien Shane, Cancer Cell . 2019,第1期

机译：I型PRMT抑制剂，GSK3368715的抗肿瘤活性，通过MTAP损失来协同PRMT5抑制
2. P3.03-005 Inhibition of PRMT5 is Synthetic Lethal in Mesotheliomas Harboring MTAP Loss [J] . Annabel Sharkey, Luke Martinson, John Le Quesne, Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer . 2017,第1期

机译：P3.03-005 PRMT5的抑制作用是间皮瘤的合成致死，含有MTAP损失
3. P3.03-005 Inhibition of PRMT5 is Synthetic Lethal in Mesotheliomas Harboring MTAP Loss [J] . Annabel Sharkey, Luke Martinson, John Le Quesne, Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer . 2017,第1期

机译：P3.03-005 PRMT5的抑制作用是间皮瘤的合成致死，含有MTAP损失
4. Design, synthesis, and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptofic Bcl-2 family proteins: Characteristics of broad-spectrum protein binding and its effects on anti-tumor activity [C] . Can-Hui Zheng, Jia-Guo Lv, Ju Zhu, International conference of molecular simulations and applied informatics technologies . 2012

机译：抗凋亡Bcl-2家族蛋白的广谱小分子抑制剂的设计，合成和活性评估：广谱蛋白结合的特征及其对抗肿瘤活性的影响
5. Kinetic Analysis of Small Molecule Inhibitors Targeting Protein Arginine Methyltransferase-5 (PRMT5) Using Surface Plasmon Resonance (Spr) [D] . Baker, Lynn Kim. 2020

机译：用表面等离子体共振（SPR）靶向蛋白质精氨酸甲基转移酶-5（PRMT5）的小分子抑制剂的动力学分析
6. PRMT1 loss sensitizes cells to PRMT5 inhibition [O] . Guozhen Gao, Liang Zhang, Oscar D Villarreal, 2019

机译：PRMT1丢失使细胞对PRMT5抑制敏感
7. Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss [O] . Andrew Fedoriw, Satyajit R. Rajapurkar, Shane OBrien, 2019

机译：I型PRMT抑制剂，GSK3368715的抗肿瘤活性，通过MTAP损失来协同PRMT5抑制
8. PARP Inhibitors Synergize With Loss of Checkpoint Control to Kill Mammary Carcinoma Cells [R] . Dent, P., Tang, Y. 2011

机译：paRp抑制剂协同失去检查点控制以杀死乳腺癌细胞

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

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