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

07 July 2020, Version 1

Abstract

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.

Keywords

kinase
Chemical Probe
X-ray crystal structure determination
Molecular Dynamics Simulation Study

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Now Published

A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation [opens in a new tab]
Alfredo Picado, Apirat Chaikuad, Carrow I. Wells, Safal Shrestha, William J. Zuercher, Julie E. Pickett, Frank E. Kwarcinski, Parvathi Sinha, Chandi S. de Silva, Reena Zutshi, Shubin Liu, Natarajan Kannan, Stefan Knapp, David H. Drewry, Timothy M. Willson journal article
Journal of Medicinal Chemistry , Volume 63, Issue 23
Online publication date: Nov 20, 2020

Version History

Jul 07, 2020 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.12616178.v1
D O I: 10.26434/chemrxiv.12616178.v1 [opens in a new tab]

Funding

1R44TR001916-02
1R01CA218442-01
1U24DK116204-01
1U01CA239106-01

Author’s competing interest statement

No conflict of interest

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