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Novel Hinge‐Binding Motifs for Janus Kinase 3 Inhibitors: A Comprehensive Structure–Activity Relationship Study on Tofacitinib Bioisosteres
Author(s) -
Gehringer Matthias,
Forster Michael,
Pfaffenrot Ellen,
Bauer Silke M.,
Laufer Stefan A.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402252
Subject(s) - tofacitinib , pharmacophore , janus kinase , in silico , computational biology , structural motif , ruxolitinib , chemistry , kinase , tyrosine kinase 2 , tyrosine kinase , stereochemistry , pharmacology , biochemistry , biology , myelofibrosis , signal transduction , gene , receptor , immunology , rheumatoid arthritis , bone marrow , platelet derived growth factor receptor , growth factor
The Janus kinases (JAKs) are a family of cytosolic tyrosine kinases crucially involved in cytokine signaling. JAKs have been demonstrated to be valid targets in the treatment of inflammatory and myeloproliferative disorders, and two inhibitors, tofacitinib and ruxolitinib, recently received their marketing authorization. Despite this success, selectivity within the JAK family remains a major issue. Both approved compounds share a common 7 H‐ pyrrolo[2,3‐ d ]pyrimidine hinge binding motif, and little is known about modifications tolerated at this heterocyclic core. In the current study, a library of tofacitinib bioisosteres was prepared and tested against JAK3. The compounds possessed the tofacitinib piperidinyl side chain, whereas the hinge binding motif was replaced by a variety of heterocycles mimicking its pharmacophore. In view of the promising expectations obtained from molecular modeling, most of the compounds proved to be poorly active. However, strategies for restoring activity within this series of novel chemotypes were discovered and crucial structure–activity relationships were deduced. The compounds presented may serve as starting point for developing novel JAK inhibitors and as a valuable training set for in silico models.