Successful computational prediction of the structure-activity relationship of a potent JAK2 inhibitor

JAK2 is a member of the JAK family of protein tyrosine kinases (PTK). JAK2 is an important intracellular mediator of cytokine signaling and its mutants are involved in haematological cancers and other chronic diseases. The specificity of inhibitors targeting the JAK2 PTK domain, particularly over other JAK kinases, is a critical design element of clinically relevant drugs. Due to the considerable structural similarity amongst the over 500 kinases in the human genome, designing a highly specific inhibitor of just one kinase is a nontrivial task. We have performed molecular docking studies of a high-affinity pan-JAK inhibitor (tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one) into a JAK2 PTK structure using our in-house software ChemaPhore™. Lacking an X-ray structure, the studies were based initially on a homology model of JAK2. In order to improve the specificity and potency of the inhibitors, a series of modifications to the pan-JAK inhibitor were suggested and the new compounds were then synthesized and biologically tested. The results of the structure-activity relationship (SAR) obtained from wet screening are consistent with the proposed binding mode of the pan-JAK inhibitor. More importantly, recent X-ray crystal structures of JAK2 inhibitor complexes are consistent with our JAK2 homology model and confirm our predictions. PRIB 2008 proceedings found at: http://dx.doi.org/10.1007/978-3-540-88436-1 Contributors: Monash University. Faculty of Information Technology. Gippsland School of Information Technology ; Chetty, Madhu ; Ahmad, Shandar ; Ngom, Alioune ; Teng, Shyh Wei ; Third IAPR International Conference on Pattern Recognition in Bioinformatics (PRIB) (3rd : 2008 : Melbourne, Australia) ; Coverage: Rights: Copyright by Third IAPR International Conference on Pattern Recognition in Bioinformatics. All rights reserved.