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本文引用的文献

1
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development.GDC-0853 的发现：一种在早期临床开发中具有强大、选择性和非共价结合的布鲁顿酪氨酸激酶抑制剂。
J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712. Epub 2018 Feb 23.
2
Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile.阿卡拉布替尼（ACP-196）：一种具有独特选择性和体内药效学特征的共价布鲁顿酪氨酸激酶抑制剂。
J Pharmacol Exp Ther. 2017 Nov;363(2):240-252. doi: 10.1124/jpet.117.242909. Epub 2017 Sep 7.
3
Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling.布鲁顿酪氨酸激酶抑制剂螯合Y551并阻止磷酸化的能力决定了其抑制Fc受体而非B细胞受体信号传导的效力。
Mol Pharmacol. 2017 Mar;91(3):208-219. doi: 10.1124/mol.116.107037. Epub 2017 Jan 6.
4
How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction.活性代谢产物如何引发免疫反应，而这种反应有时会导致特异质性药物反应。
Chem Res Toxicol. 2017 Jan 17;30(1):295-314. doi: 10.1021/acs.chemrestox.6b00357. Epub 2016 Nov 8.
5
Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers.6-氟-5-(R)-(3-(S)-(8-氟-1-甲基-2,4-二氧代-1,2-二氢喹唑啉-3(4H)-基)-2-甲基苯基)-2-(S)-(2-羟基丙烷-2-基)-2,3,4,9-四氢-1H-咔唑-8-甲酰胺（BMS-986142）的发现：一种由两种锁定的阻转异构体构象受限的布鲁顿酪氨酸激酶（BTK）可逆抑制剂。
J Med Chem. 2016 Oct 13;59(19):9173-9200. doi: 10.1021/acs.jmedchem.6b01088. Epub 2016 Sep 19.
6
Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus.靶向B细胞疗法在成人及儿童系统性红斑狼疮治疗中的应用
Lupus. 2016 Sep;25(10):1086-96. doi: 10.1177/0961203316652491.
7
The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy.布鲁顿酪氨酸激酶在自身免疫中的作用及治疗意义。
Expert Rev Clin Immunol. 2016 Jul;12(7):763-73. doi: 10.1586/1744666X.2016.1152888. Epub 2016 Mar 4.
8
BTK Signaling in B Cell Differentiation and Autoimmunity.B细胞分化和自身免疫中的BTK信号传导
Curr Top Microbiol Immunol. 2016;393:67-105. doi: 10.1007/82_2015_478.
9
Prolonged and tunable residence time using reversible covalent kinase inhibitors.使用可逆共价激酶抑制剂实现延长且可调节的停留时间。
Nat Chem Biol. 2015 Jul;11(7):525-31. doi: 10.1038/nchembio.1817. Epub 2015 May 25.
10
The ABC of protein kinase conformations.蛋白激酶构象基础
Biochim Biophys Acta. 2015 Oct;1854(10 Pt B):1555-66. doi: 10.1016/j.bbapap.2015.03.009. Epub 2015 Apr 1.

氨基吡唑甲酰胺类布鲁顿酪氨酸激酶抑制剂。从不可逆到可逆的共价反应基团调控

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning.

作者信息

Schnute Mark E, Benoit Stephen E, Buchler Ingrid P, Caspers Nicole, Grapperhaus Margaret L, Han Seungil, Hotchandani Rajeev, Huang Nelson, Hughes Robert O, Juba Brian M, Kim Kyung-Hee, Liu Erica, McCarthy Erin, Messing Dean, Miyashiro Joy S, Mohan Shashi, O'Connell Thomas N, Ohren Jeffrey F, Parikh Mihir D, Schmidt Michelle, Selness Shaun R, Springer John R, Thanabal Venkataraman, Trujillo John I, Walker Daniel P, Wan Zhao-Kui, Withka Jane M, Wittwer Arthur J, Wood Nancy L, Xing Li, Zapf Christoph W, Douhan John

机构信息

Medicine Design and Inflammation and Immunology Research, Pfizer, Cambridge, Massachusetts 02139, United States.

Medicine Design, Pfizer, Groton, Connecticut 06340, United States.

出版信息

ACS Med Chem Lett. 2018 Dec 3;10(1):80-85. doi: 10.1021/acsmedchemlett.8b00461. eCollection 2019 Jan 10.

DOI:10.1021/acsmedchemlett.8b00461
PMID:30655951
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6331194/
Abstract

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

摘要

已鉴定出基于氨基吡唑甲酰胺支架的布鲁顿酪氨酸激酶（BTK）的强效共价抑制剂。与导致不可逆蛋白质加合物的基于丙烯酰胺的共价反应基团相比，基于氰胺的可逆共价抑制剂具有最高的BTK效力和EGFR选择性组合。通过酶动力学、核磁共振、质谱和X射线晶体学研究证实了氰胺与BTK的共价机制。基于氰胺的先导抑制剂表现出优异的激酶组选择性和大鼠药代动力学特性。