Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

JaredT. Hammill; Deepak Bhasin; Daniel C. Scott; Jaeki Min; Yizhe Chen; Yan Lu; Lei Yang; Ho Shin Kim; Michele C. Connelly; Courtney Hammill; Gloria Holbrook; Cynthia Jeffries; Bhuvanesh Singh; Brenda A. Schulman; R. Kiplin Guy

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Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

机译：发现口服生物可爱的缺陷型在Cullin Neddylation 1（DCN1）介导的Cullin Neddylation中的缺陷抑制剂

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机译：<！[CDATA [我们之前报道了一系列哌啶基脲的发现，验证和结构 - 活动关系，其效果抑制DCN1-UBE2M相互作用。我们证明，化合物 7在生化测定中抑制DCN1-UBE2M蛋白 - 蛋白质相互作用和DCN1介导的Cullin Neddylation，并降低了含DCN1扩增的鳞状癌细胞系中的稳态Cullin Neddylation的水平。虽然化合物 7表现出良好的溶解度和渗透性，但它在微粒体模型中迅速代谢（CL_（int）= 170ml / min / kg）。这项工作列出了口头生物可利用的模拟，NACM-opt（ 67）的发现。化合物 67保留了化合物 7的有利生物化学和细胞活性，但在体外和体内显着稳定。化合物 67是口服生物可利用的，在小鼠中耐受良好耐受，目前用于研究急性药理学抑制DCN1-UBE2M相互作用对NEDD8 / CUL途径的影响。]> 展开▼

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《Journal of Medicinal Chemistry》 |2018年第7期|共13页

作者
JaredT. Hammill; Deepak Bhasin; Daniel C. Scott; Jaeki Min; Yizhe Chen; Yan Lu; Lei Yang; Ho Shin Kim; Michele C. Connelly; Courtney Hammill; Gloria Holbrook; Cynthia Jeffries; Bhuvanesh Singh; Brenda A. Schulman; R. Kiplin Guy;
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Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Howard Hughes Medical Institute St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Surgery Laboratory of Epithelial Cancer Biology Memorial Sloan Kettering Cancer Center New York New York 10065 United States;

Howard Hughes Medical Institute St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

Department of Chemical Biology and Theraputics St. Jude Children’s Research Hospital Memphis Tennessee 38105 United States;

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正文语种 eng

中图分类药学;

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1. miR-148b-3p promotes migration of Schwann cells by targeting cullin-associated and neddylation-dissociated 1 [J] . Tian-mei Qian, Song-lin Zhou, Li-li Zhao, 中国神经再生研究（英文版） . 2016,第006期

2. Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation [J] . JaredT. Hammill, Deepak Bhasin, Daniel C. Scott, Journal of Medicinal Chemistry . 2018,第7期

机译：发现口服生物可爱的缺陷型在Cullin Neddylation 1（DCN1）介导的Cullin Neddylation中的缺陷抑制剂

3. Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation [J] . Kim Ho Shin, Hammill Jared T., Scott Daniel C., Journal of Medicinal Chemistry . 2019,第18期

机译：发现新型吡唑-吡啶酮DCN1抑制剂控制Cullin Neddylation

4. Dcn1 functions as a scaffold-type E3 ligase for cullin neddylation. [J] . Kurz T, Chou YC, Willems AR, Molecular cell . 2008,第1期

机译：Dcn1充当脚手架类型E3连接酶，以促进cullin的乙二醛化。

5. CNX-774, an Irreversible, Selective and Orally Bioavailable Inhibitor of Bruton's Tyrosine Kinase: In Vitro ADME, Selectivity, and Pharmacokinetic Properties [C] . Prasoon Chaturvedi, Matthew Labenski, Erica Evans, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2011

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7. Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-mediated Cullin Neddylation [O] . Jared T. Hammill, Deepak Bhasin, Daniel C. Scott, -1

机译：在Cullin Neddylation 1（DCN1）介导的Cullin Neddylation中有缺陷的口服生物利用抑制剂的发现。

8. Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation [O] . Jared T. Hammill, Deepak Bhasin, Daniel C. Scott, 2018

机译：发现口服生物可爱的缺陷型在Cullin Neddylation 1（DCN1）介导的Cullin Neddylation中的缺陷抑制剂

9. Regulation of Ubiquitin Mediated Proteolysis of G1 Cyclins and the CDK Inhibitor p27 by the Cullin Gene Family in Normal Tumorigenic Human Breast Cells [R] . McCarville, J. , Xiong, Y. 2001

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2. Cullin-RING E3泛素连接酶及其抑制剂在肿瘤治疗中的研究进展 [J] . 韦琼 ,陈锦飞 . 东南大学学报（医学版） . 2017,第001期

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5. 复制缺陷型病毒载体介导的hFⅤⅢ cDNA在动物体内表达的初步研究 [C] . 姜志龙 ,卢健 . 第八次全国生物化学与分子生物学学术会议 . 1997

6. 家族性高血钾型高血压Cullin 3致病突变体neddylation异常的分子机制研究 [A] . 牛伟 . 2015

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Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

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