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The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-03-23 , DOI: 10.1021/acs.jmedchem.0c02083 Ryan V Quiroz 1 , Michael H Reutershan 1 , Sebastian E Schneider 1 , David Sloman 1 , Brian M Lacey 1 , Brooke M Swalm 1 , Charles S Yeung 1 , Craig Gibeau 1 , Daniel S Spellman 2 , Danica A Rankic 1 , Dapeng Chen 1 , David Witter 1 , Doug Linn 1 , Erik Munsell 1 , Guo Feng 1 , Haiyan Xu 1 , Jonathan M E Hughes 3 , Jongwon Lim 1 , Josep Saurí 1 , Kristin Geddes 2 , Murray Wan 1 , My Sam Mansueto 1 , Nicole E Follmer 1 , Patrick S Fier 3 , Phieng Siliphaivanh 1 , Pierre Daublain 1 , Rachel L Palte 1 , Robert P Hayes 2 , Sandra Lee 3 , Shuhei Kawamura 1 , Steven Silverman 3 , Sulagna Sanyal 1 , Timothy J Henderson 1 , Yingchun Ye 1 , Yuanwei Gao 2 , Benjamin Nicholson 1 , Michelle R Machacek 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-03-23 , DOI: 10.1021/acs.jmedchem.0c02083 Ryan V Quiroz 1 , Michael H Reutershan 1 , Sebastian E Schneider 1 , David Sloman 1 , Brian M Lacey 1 , Brooke M Swalm 1 , Charles S Yeung 1 , Craig Gibeau 1 , Daniel S Spellman 2 , Danica A Rankic 1 , Dapeng Chen 1 , David Witter 1 , Doug Linn 1 , Erik Munsell 1 , Guo Feng 1 , Haiyan Xu 1 , Jonathan M E Hughes 3 , Jongwon Lim 1 , Josep Saurí 1 , Kristin Geddes 2 , Murray Wan 1 , My Sam Mansueto 1 , Nicole E Follmer 1 , Patrick S Fier 3 , Phieng Siliphaivanh 1 , Pierre Daublain 1 , Rachel L Palte 1 , Robert P Hayes 2 , Sandra Lee 3 , Shuhei Kawamura 1 , Steven Silverman 3 , Sulagna Sanyal 1 , Timothy J Henderson 1 , Yingchun Ye 1 , Yuanwei Gao 2 , Benjamin Nicholson 1 , Michelle R Machacek 1
Affiliation
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Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest. Described herein are the structure-based drug designs, robust synthetic efforts, and lead optimization strategies toward the identification of two novel 5,5-fused bicyclic nucleoside-derived classes of potent and efficacious PRMT5 inhibitors. Utilization of compound docking and strain energy calculations inspired novel designs, and the development of flexible synthetic approaches enabled access to complex chemotypes with five contiguous stereocenters. Additional efforts in balancing bioavailability, solubility, potency, and CYP3A4 inhibition led to the identification of diverse lead compounds with favorable profiles, promising in vivo activity, and low human dose projections.
中文翻译：
两类新型 5,5-双环核苷衍生 PRMT5 抑制剂的发现，用于治疗癌症
蛋白质精氨酸甲基转移酶 5 (PRMT5) 是一种 II 型精氨酸甲基转移酶，可催化蛋白质底物的翻译后对称二甲基化。 PRMT5 在调节生物过程中发挥着关键作用，包括转录、细胞周期进程、RNA 剪接和 DNA 修复。因此，PRMT5 活性的失调与多种癌症的发生和进展有关，并且是临床日益关注的目标。本文描述了基于结构的药物设计、稳健的合成工作以及用于鉴定两种新型 5,5-融合双环核苷衍生类强效 PRMT5 抑制剂的先导化合物优化策略。化合物对接和应变能计算的利用激发了新颖的设计，灵活的合成方法的开发使得能够获得具有五个连续立体中心的复杂化学型。在平衡生物利用度、溶解度、效力和 CYP3A4 抑制方面的额外努力导致鉴定出具有良好特性、有前景的体内活性和低人体剂量预测的多种先导化合物。
更新日期：2021-04-08
中文翻译：
两类新型 5,5-双环核苷衍生 PRMT5 抑制剂的发现，用于治疗癌症
蛋白质精氨酸甲基转移酶 5 (PRMT5) 是一种 II 型精氨酸甲基转移酶，可催化蛋白质底物的翻译后对称二甲基化。 PRMT5 在调节生物过程中发挥着关键作用，包括转录、细胞周期进程、RNA 剪接和 DNA 修复。因此，PRMT5 活性的失调与多种癌症的发生和进展有关，并且是临床日益关注的目标。本文描述了基于结构的药物设计、稳健的合成工作以及用于鉴定两种新型 5,5-融合双环核苷衍生类强效 PRMT5 抑制剂的先导化合物优化策略。化合物对接和应变能计算的利用激发了新颖的设计，灵活的合成方法的开发使得能够获得具有五个连续立体中心的复杂化学型。在平衡生物利用度、溶解度、效力和 CYP3A4 抑制方面的额外努力导致鉴定出具有良好特性、有前景的体内活性和低人体剂量预测的多种先导化合物。
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