SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K

Carrow Wells; Rafael M Couñago; Juanita C Limas; Tuanny L Almeida; Jeanette Gowen Cook; David H Drewry; Jonathan M Elkins; Opher Gileadi; Nirav R Kapadia; Alvaro Lorente-Macias; Julie E Pickett; Alexander Riemen; Roberta R Ruela-de-Sousa; Timothy M Willson; Cunyu Zhang; William J Zuercher; Reena Zutshi; Alison D Axtman

doi:10.1021/acsmedchemlett.9b00399

SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K

ACS Med Chem Lett. 2019 Oct 23;11(3):340-345. doi: 10.1021/acsmedchemlett.9b00399. eCollection 2020 Mar 12.

Authors

Carrow Wells^{1

2}, Rafael M Couñago^{3

4}, Juanita C Limas⁵, Tuanny L Almeida^{3

4}, Jeanette Gowen Cook⁶, David H Drewry^{1

2}, Jonathan M Elkins^{3

7}, Opher Gileadi^{3

7}, Nirav R Kapadia^{1

2}, Alvaro Lorente-Macias⁸, Julie E Pickett^{1

2}, Alexander Riemen⁹, Roberta R Ruela-de-Sousa^{3

4}, Timothy M Willson^{1

2}, Cunyu Zhang¹⁰, William J Zuercher^{1

2

11}, Reena Zutshi⁹, Alison D Axtman^{1

2}

Affiliations

¹ 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.
² Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, UNC-CH, Chapel Hill, North Carolina 27599, United States.
³ SGC, Departamento de Genética e Evolução, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-886, Brazil.
⁴ Centro de Química Medicinal, Centro de Biologia Molecular e Engenharia Genética, UNICAMP, Campinas, SP 13083-875, Brazil.
⁵ Department of Pharmacology, UNC-CH, Chapel Hill, North Carolina 27599, United States.
⁶ Department of Biochemistry and Biophysics, UNC-CH, Chapel Hill, North Carolina 27599, United States.
⁷ SGC, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, U.K.
⁸ Departamento de Química Farmacéutica y Orgánica, University of Granada, Granada, 18071, Spain.
⁹ Luceome Biotechnologies, LLC, Tucson, Arizona 85719, United States.
¹⁰ Platform Technology Sciences, GlaxoSmithKline, Collegeville, Pennsylvania 19426, United States.
¹¹ Lineberger Comprehensive Cancer Center (LCCC), UNC-CH, Chapel Hill, North Carolina 27599, United States.

Abstract

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.

Abstract

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