Journal Article

PUBDB-2021-00360

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation

Picado, A. ; Chaikuad, A. ; Wells, C. I. ; Shrestha, S. ; Zuercher, W. J. ; Pickett, J. E. ; Kwarcinski, F. E. ; Sinha, P. ; de Silva, C. S. ; Zutshi, R. ; Liu, S. ; Kannan, N. ; Knapp, S. ; Drewry, D. H. ; Willson, T. M. (Corresponding author)

2020
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.0c01174  doi:10.3204/PUBDB-2021-00360

Abstract: STK17B is a member of the death-associated protein kinase family and has been genetically linked to the development of diverse diseases. However, the role of STK17B in normal and disease pathology is poorly defined. Here, we present the discovery of thieno[3,2-d] pyrimidine SGC-STK17B-1 (11s), a high-quality chemical probe for this understudied “dark” kinase. 11s is an ATP-competitive inhibitor that showed remarkable selectivity over other kinases including the closely related STK17A. X-ray crystallography of 11s and related thieno[3,2-d]pyrimidines bound to STK17B revealed a unique P-loop conformation characterized by a salt bridge between R41 and the carboxylic acid of the inhibitor. Molecular dynamic simulations of STK17B revealed the flexibility of the P-loop and a wide range of R41 conformations available to the apo-protein. The isomeric thieno[2,3-d]pyrimidine SGC-STK17B-1N (19g) was identified as a negative control compound. The >100-fold lower activity of 19g on STK17B was attributed to the reduced basicity of its pyrimidine N1.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2020

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Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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