Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012.
BACKGROUND
Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles. More selective JAK2 or JAK3 compounds are now coming through in considerable numbers and this review attempts to provide an update of the recent patent literature of those new compounds. An overview is given on the diversity of core structures employed for inhibitor design showing that the vast majority of compounds are based on classic ATP-competitive kinase inhibitor heterocycles.


METHODS
This review updates new patents claiming JAK2 and/or JAK3 inhibitors published from 2010 to 2012. Pre-2010 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. This review does not cover JAK1 or TYK2 inhibitors but mention is made of these where they occur within series of JAK2/3 inhibitors. Given the overlap between many pharmacophores, it was not possible to completely separate inhibitors of JAK2 from JAK3, hence the material is organized by JAK2, JAK3 and JAK2/3 and within each section by alphabetical order of the patent assignee, some companies having published five or more patents, such as Ambit (10), Incyte (9), Galapagos (7), Almirall (6) and Biocryst (5). A total of 98 patents are reviewed herein.


CONCLUSIONS
JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development. Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling. The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic. These advances are expected to lead to further significant progress improving patient outcomes and quality of life.
National University of Singapore, Faculty of Science, Department of Pharmacy, Singapore. phadbw@nus.edu.sg
Brian W
BW
Dymock
Cheng Shang
CS
See
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004335:Drug and Narcotic Control; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010330:Patents as Topic; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2; D053616:Janus Kinase 3