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

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

  • J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174.
Alfredo Picado 1,  Apirat Chaikuad 2 3,  Carrow I Wells 1,  Safal Shrestha 4,  William J Zuercher 1,  Julie E Pickett 1,  Frank E Kwarcinski 5,  Parvathi Sinha 5,  Chandi S de Silva 5,  Reena Zutshi 5,  Shubin Liu 6,  Natarajan Kannan 4 7,  Stefan Knapp 2 3 8 9,  David H Drewry 1,  Timothy M Willson 1
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, United States.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, Frankfurt 60438, Germany.
  • 3 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Max-von-Laue-Straße 15, Frankfurt 60438, Germany.
  • 4 Institute of Bioinformatics, University of Georgia, Athens, Georgia 30602, United States.
  • 5 Luceome Biotechnologies, 1665 E. 18th Street, Suite 106, Tucson, Arizona 85719, United States.
  • 6 Research Computing Center, University of North Carolina, Chapel Hill, North Carolina 27599-3420, United States.
  • 7 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, United States.
  • 8 German Translational Cancer Network (DKTK) site Frankfurt/Mainz, Frankfurt am Main 60596, Germany.
  • 9 Frankfurt Cancer Institute (FCI), Paul-Ehrlich-Straße 42-44, Frankfurt am Main 60596, Germany.
PMID: 33215924 DOI: 10.1021/acs.jmedchem.0c01174
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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