Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK)

Giancarlo Trani; John J Barker; Steven M Bromidge; Frederick A Brookfield; Jason D Burch; Yuan Chen; Charles Eigenbrot; Alexander Heifetz; M Hicham A Ismaili; Adam Johnson; Thomas M Krülle; Colin H MacKinnon; Rosemary Maghames; Paul A McEwan; Christian A G N Montalbetti; Daniel F Ortwine; Yolanda Pérez-Fuertes; Darshan G Vaidya; Xiaolu Wang; Ali A Zarrin; Zhonghua Pei

doi:10.1016/j.bmcl.2014.10.020

Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK)

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5818-5823. doi: 10.1016/j.bmcl.2014.10.020. Epub 2014 Oct 12.

Authors

Giancarlo Trani¹, John J Barker², Steven M Bromidge², Frederick A Brookfield², Jason D Burch³, Yuan Chen³, Charles Eigenbrot³, Alexander Heifetz², M Hicham A Ismaili³, Adam Johnson³, Thomas M Krülle², Colin H MacKinnon², Rosemary Maghames², Paul A McEwan², Christian A G N Montalbetti², Daniel F Ortwine³, Yolanda Pérez-Fuertes², Darshan G Vaidya², Xiaolu Wang⁴, Ali A Zarrin³, Zhonghua Pei³

Affiliations

¹ Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK. Electronic address: Giancarlo.Trani@evotec.com.
² Discovery Chemistry, Evotec UK Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, UK.
³ Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
⁴ Discovery Biology, Evotec AG, Manfred Eigen Campus, Essener Bogen 7, D-22419 Hamburg, Germany.

PMID: 25455497
DOI: 10.1016/j.bmcl.2014.10.020

Abstract

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.

Keywords: ITK inhibitor; Sulfonylpyridine; T-cell receptor.

MeSH terms

Binding Sites
Crystallography, X-Ray
Drug Design*
Kinetics
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Structure, Tertiary
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Pyrazoles / chemistry
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / metabolism
Structure-Activity Relationship
Sulfones / chemistry

Substances

Protein Kinase Inhibitors
Pyrazoles
Pyridines
Sulfones
pyrazole
Protein-Tyrosine Kinases
emt protein-tyrosine kinase
pyridine