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

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

doi:10.26434/chemrxiv.12616178.v1

Biological and Medicinal Chemistry

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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

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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.

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A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation

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