SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K,ACS Medicinal Chemistry Letters

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SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-10-29 , DOI: 10.1021/acsmedchemlett.9b00399
Carrow Wells _{1,

2} , Rafael M Couñago _{3,

4} , Juanita C Limas ₅ , Tuanny L Almeida _{3,

4} , Jeanette Gowen Cook ₆ , David H Drewry _{1,

2} , Jonathan M Elkins _{3,

7} , Opher Gileadi _{3,

7} , Nirav R Kapadia _{1,

2} , Alvaro Lorente-Macias ₈ , Julie E Pickett _{1,

2} , Alexander Riemen ₉ , Roberta R Ruela-de-Sousa _{3,

4} , Timothy M Willson _{1,

2} , Cunyu Zhang ₁₀ , William J Zuercher _{1,

2,

11} , Reena Zutshi ₉ , Alison D Axtman _{1,

2}

Affiliation

Structural Genomics Consortium (SGC), UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill (UNC-CH), Chapel Hill, North Carolina 27599, United States.
Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, Chapel Hill, North Carolina 27599, United States.
SGC, Departamento de Genética e Evolução, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-886, Brazil.
Centro de Química Medicinal, Centro de Biologia Molecular e Engenharia Genética, UNICAMP, Campinas, SP 13083-875, Brazil.
Department of Pharmacology, UNC-CH, Chapel Hill, North Carolina 27599, United States.
Department of Biochemistry and Biophysics, UNC-CH, Chapel Hill, North Carolina 27599, United States.
SGC, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, U.K.
Departamento de Química Farmacéutica y Orgánica, University of Granada, Granada, 18071, Spain.
Luceome Biotechnologies, LLC, Tucson, Arizona 85719, United States.
Platform Technology Sciences, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States.
Lineberger Comprehensive Cancer Center (LCCC), UNC-CH, Chapel Hill, North Carolina 27599, United States.

Inhibitors based on a 3-acylaminoindazole scaffold were synthesized to yield potent dual AAK1/BMP2K inhibitors. Optimization furnished a small molecule chemical probe (SGC-AAK1-1, 25) that is potent and selective for AAK1/BMP2K over other NAK family members, demonstrates narrow activity in a kinome-wide screen, and is functionally active in cells. This inhibitor represents one of the best available small molecule tools to study the functions of AAK1 and BMP2K.

中文翻译：

SGC-AAK1-1：针对 AAK1 和 BMP2K 的化学探针

合成基于 3-酰基氨基吲唑支架的抑制剂以产生有效的双重 AAK1/BMP2K 抑制剂。优化提供了一种小分子化学探针 (SGC-AAK1-1, 25 )，该探针对 AAK1/BMP2K 比其他 NAK 家族成员更有效且具有选择性，在整个激酶组筛选中表现出较窄的活性，并且在细胞中具有功能活性。这种抑制剂代表了研究 AAK1 和 BMP2K 功能的最佳可用小分子工具之一。

更新日期：2019-10-29

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