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A Chemical Probe Targeting AAK1 and BMP2K

04 September 2019, Version 1

Abstract

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.

Keywords

AAK1
BMP2K
NAK Family
Endocytosis
Protein kinase
acylaminoindazole

Supplementary materials

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Description
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ACS MCL experimental final
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Now Published

SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K [opens in a new tab]
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 journal article
ACS Medicinal Chemistry Letters , Volume 11, Issue 3
Online publication date: Oct 23, 2019

Version History

Sep 04, 2019 Version 1

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv.9756785.v1
D O I: 10.26434/chemrxiv.9756785.v1 [opens in a new tab]

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
National Center for Advancing Translational Sciences
R44TR001916
Tools for Accelerating R&D for Historically Understudied Protein Kinases
https://app.dimensions.ai/details/grant/grant.6617154 [opens in a new tab]
Government of Spain-Ministry of Education, Culture and Sports/College of Spain - Training programme for Academic Staff (FPU grant ref. 14/00818)
National Institute of Allergy and Infectious Diseases
UM2AI130836
NEW HORIZONS IN THE PREVENTION AND TREATMENT OF FOOD ALLERGY
https://app.dimensions.ai/details/grant/grant.6617382 [opens in a new tab]
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
National Institute of General Medical Sciences
R25GM089569
UNC PREP in the Biomedical Sciences
https://app.dimensions.ai/details/grant/grant.2623406 [opens in a new tab]
National Institute of General Medical Sciences
T32GM007040
Predoctoral Training in Pharmacological Sciences
https://app.dimensions.ai/details/grant/grant.2683656 [opens in a new tab]
National Cancer Institute
P30CA016086
Cancer Center Support Grant
https://app.dimensions.ai/details/grant/grant.2438821 [opens in a new tab]
HHMI Gilliam Fellowship for Advanced Study (GT10886)
National Institute of General Medical Sciences
R01GM083024
Replication Licensing and the Cell Cycle
https://app.dimensions.ai/details/grant/grant.2519811 [opens in a new tab]
FAPESP/5087-0/2014
FAPESP/17469-0/2016

Author’s competing interest statement

The authors declare no conflict of interest.

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