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A Chemical Probe for Dark Kinase STK17B Derives its Potency and High Selectivity Through a Unique P-loop Conformation

preprint
submitted on 06.07.2020 and posted on 07.07.2020 by Alfredo Picado, Apirat Chaikuad, Carrow Wells, Safal Shrestha, William Zuercher, Julie E. Pickett, Frank Kwarcinski, Parvathi Sinha, Chandi de Silva, Reena Zutshi, Shubin Liu, Natarajan Kannan, Stefan Knapp, David Drewry, Tim Willson
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.

Funding

1R44TR001916-02

1R01CA218442-01

1U24DK116204-01

1U01CA239106-01

History

Email Address of Submitting Author

tim.willson@unc.edu

Institution

University of North Carolina at Chapel Hill

Country

United States

ORCID For Submitting Author

0000-0003-4181-8223

Declaration of Conflict of Interest

No conflict of interest

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