Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease

Van de Poel Amanda; Toledo-Sherman Leticia; Breccia Perla; Cachope Roger; Bate Jennifer R.; Angulo-Herrera Ivan; Wishart Grant; Matthews Kim L.; Martin Sarah L.; Peacock Marcus; Barnard Amy; Cox Helen C.; Jones Graham; McAllister George; Vater Huw; Esmieu William; Clissold Cole; Lamers Marieke; Leonard Philip; Jarvis Rebecca E.; Blackaby Wesley; Eznarriaga Maria; Lazari Ovadia; Yates Dawn; Rose Mark; Jang Sung-Wook; Munoz-Sanjuan Ignacio; Dominguez Celia

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Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease

机译：亨廷顿疾病中ATM抑制剂选择性的基于结构探索

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Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

机译：我们的研究小组最近发现，脑渗透性共济失调毛细血管扩张突变（ATM）激酶抑制剂可能是治疗亨廷顿病（HD）的新疗法。然而，之前描述的吡喃酮硫杂蒽（例如4）未能提供对空泡蛋白分选34（Vps34）激酶的选择性，该激酶是一种与自噬有关的重要激酶。鉴于自噬受损已被认为是HD等神经退行性疾病的致病机制，实现对Vps34的选择性成为我们项目的一个重要目标。在这里，我们报告了通过使用Vps34-ATM蛋白嵌合体的X射线晶体结构成功优化ATM对Vps34的选择性，其中Vps34-ATP结合位点突变为近似于ATM激酶的位点。由于该选择性优化过程，吗啉基吡啶酮和吗啉基嘧啶酮系列具有较高的ATM效价和良好的口服生物利用度，并且与吡喃酮硫杂蒽相比，具有较低的分子量、较低的亲脂性、较高的水溶性和更大的合成可处理性。

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来源
《Journal of Medicinal Chemistry》 |2021年第8期|共19页
作者
Van de Poel Amanda; Toledo-Sherman Leticia; Breccia Perla; Cachope Roger; Bate Jennifer R.; Angulo-Herrera Ivan; Wishart Grant; Matthews Kim L.; Martin Sarah L.; Peacock Marcus; Barnard Amy; Cox Helen C.; Jones Graham; McAllister George; Vater Huw; Esmieu William; Clissold Cole; Lamers Marieke; Leonard Philip; Jarvis Rebecca E.; Blackaby Wesley; Eznarriaga Maria; Lazari Ovadia; Yates Dawn; Rose Mark; Jang Sung-Wook; Munoz-Sanjuan Ignacio; Dominguez Celia;
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Charles River Saffron Walden CB10 1XL Essex England;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

Charles River Saffron Walden CB10 1XL Essex England;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

Charles River Saffron Walden CB10 1XL Essex England;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

CHDI Fdn CHDI Management Los Angeles CA 90045 USA;

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中图分类药学;
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专利

1. Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington＇s disease [J] . Jeffrey R CANTLE, Xiao-Hong LU, Xiaofeng GU, 物理学前沿：英文版 . 2012,第005期
2. Identification of Novel HSP90α/β Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington's Disease [J] . Justin T. Ernst, Timothy Neubert, Michael Liu, Journal of Medicinal Chemistry . 2014,第8期

机译：使用基于结构的药物设计鉴定新型HSP90α/β亚型选择性抑制剂。证明在治疗中枢神经系统疾病（如亨廷顿氏病）方面的潜在效用
3. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease [J] . Tidball Andrew M., Bryan Miles R., Uhouse Michael A., Human Molecular Genetics . 2015,第7期

机译：在亨廷顿舞蹈病的基于患者的神经祖细胞和小鼠纹状体模型中，有选择地削弱了新型的依赖锰的ATM-p53信号通路
4. Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity-Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases [J] . ErnstJ.T., LiuM., ZuccolaH., Bioorganic and Medicinal Chemistry Letters . 2014,第1期

机译：HSP90α/β的化学型依赖性结合构象与同工型选择性之间的相关性-对基于结构设计的HSP90α/β选择性抑制剂治疗神经退行性疾病的意义
5. Isolated Synaptosomes from Cortex and Striatum of Huntington Disease Mice Show Selective Loss of Synaptosome-Specific Proteins but No Bioenergetics Deficit [C] . Birgit Schilling, R. Ng, J. Holcomb, ASMS Conference on Mass Spectrometry and Allied Topics . 2014

机译：来自皮质的孤立的突触体和亨廷顿疾病小鼠的纹状体表现出突触肌肉组特异性蛋白的选择性丧失，但没有生物共生学赤字
6. Fragment-based library screening and structure-based optimization of selective inhibitors for protozoan diseases [D] . Shibata, Sayaka 2011

机译：基于片段的文库筛选和基于结构的原生动物疾病选择性抑制剂优化
7. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntingtons disease [O] . Andrew M. Tidball, Miles R. Bryan, Michael A. Uhouse, -1

机译：在亨廷顿舞蹈病的基于患者的神经祖细胞和小鼠纹状体模型中有选择地削弱了一种新型的依赖锰的ATM-p53信号通路
8. Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington’s disease mice [O] . Amanda J Kedaigle, Jack C Reidling, Ryan G Lim, 2019

机译：用JQ1进行治疗，下注溴染色肿瘤抑制剂，对R6 / 2 Huntington的疾病小鼠选择性地有害
9. Structure-Based Design of erbB-2 Selective Small Molecule Kinase Inhibitors [R] . Wang, S. 2005

机译：基于结构的erbB-2选择性小分子激酶抑制剂的设计

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease

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