2. Academic Validation
  3. SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K

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.
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
Affiliations

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.
PMID: 32184967 DOI: 10.1021/acsmedchemlett.9b00399
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.

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