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A Chemical Probe Targeting AAK1 and BMP2K

preprint
submitted on 31.08.2019, 22:13 and posted on 04.09.2019, 16:15 by Carrow Wells, Rafael Counago, Juanita C. Limas, Tuanny L. Almeida, Jeanette G. Cook, David Drewry, Jonathan Elkins, Opher Gileadi, Nirav Kapadia, Álvaro Lorente-Macías, Julie E. Pickett, Alexander J. Riemen, Roberta R. Ruela-de-Sousa, Timothy M. Willson, Cunyu Zhang, William J. Zuercher, Reena Zutshi, Alison D. Axtman

Inhibitors based on a 3-acylaminoindazole scaffold were synthesized to yield potent dual AAK1/BMP2K inhibitors. Optimization of this 3-acylaminoindazole scaffold 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.

Funding

The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation, Takeda, and Wellcome [106169/ZZ14/Z].

FAPESP/50724-5/2013

Tools for Accelerating R&D for Historically Understudied Protein Kinases

National Center for Advancing Translational Sciences

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Government of Spain-Ministry of Education, Culture and Sports/College of Spain - Training programme for Academic Staff (FPU grant ref. 14/00818)

NEW HORIZONS IN THE PREVENTION AND TREATMENT OF FOOD ALLERGY

National Institute of Allergy and Infectious Diseases

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NC Biotech Center Institutional Support Grants 2017-IDG-1025 and 2018-IDG-1030

CNPq 465651/2014-3

Innovative Medicines Initiative ULTRA-DD grant no. 115766

UNC PREP in the Biomedical Sciences

National Institute of General Medical Sciences

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Predoctoral Training in Pharmacological Sciences

National Institute of General Medical Sciences

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Cancer Center Support Grant

National Cancer Institute

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HHMI Gilliam Fellowship for Advanced Study (GT10886)

Replication Licensing and the Cell Cycle

National Institute of General Medical Sciences

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FAPESP/5087-0/2014

FAPESP/17469-0/2016

History

Email Address of Submitting Author

Alison.Axtman@unc.edu

Institution

University of North Carolina at Chapel Hill

Country

USA

ORCID For Submitting Author

0000-0003-4779-9932

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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Read the published paper

in ACS Medicinal Chemistry Letters

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