Open AccessStructural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof
Author(s) -
Ryan R. Davis,
Baoli Li,
Sang Yun,
A. Chan,
Pradeep Nareddy,
Steven Gunawan,
Muhammad Ayaz,
Harshani R. Lawrence,
Gary W. Reuther,
Nicholas J. Lawrence,
E. Schönbrunn
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01952
Subject(s) - ruxolitinib , janus kinase 2 , chemistry , janus kinase , rheumatoid arthritis , population , small molecule , pharmacology , cancer research , kinase , biochemistry , medicine , immunology , bone marrow , myelofibrosis , environmental health
The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.