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
  • 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.

Products