Discovery of BIIB068: A Selective, Potent, Reversible Bruton's Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Journal of Medicinal Chemistry
Bin MaBrian T Hopkins

Abstract

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

References

Sep 1, 1995·Immunity·W N KhanL A Herzenberg
Aug 1, 1994·Current Opinion in Immunology·S TsukadaO N Witte
Apr 1, 1994·Immunological Reviews·C I SmithL Hammarström
May 11, 2004·International Archives of Allergy and Immunology·Uwe SchmidtWilfried Ellmeier
Sep 9, 2006·Annual Review of Medicine·Roger G Ulrich
Jan 7, 2010·Protein Science : a Publication of the Protein Society·Douglas J MarcotteLaura F Silvian
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lee A HonigbergJoseph J Buggy
Nov 30, 2010·Nature Chemical Biology·Julie A Di PaoloKevin S Currie
Mar 2, 2013·Nature Reviews. Drug Discovery·Ryan M Young, Louis M Staudt
May 28, 2013·The Journal of Pharmacology and Experimental Therapeutics·Erica K EvansWilliam F Westlin
Aug 21, 2013·Journal of Hematology & Oncology·Akintunde AkinleyeDelong Liu
Oct 4, 2013·Journal of Biomolecular Screening·Ellen L BergMark A Polokoff
Jun 28, 2015·The Journal of Surgical Research·Li XuTimothy M Pawlik
Mar 10, 2016·Journal of Hematology & Oncology·Jingjing WuDelong Liu
Sep 4, 2016·Journal of Hematology & Oncology·Jingjing WuDelong Liu
Nov 9, 2016·The Journal of Pharmacology and Experimental Therapeutics·Rebecca I EricksonDinah L Misner
Jun 22, 2017·British Journal of Clinical Pharmacology·Patrick F SmithSteve G Gourlay
Nov 24, 2017·Frontiers in Immunology·Alexander N R WeberCornelia Brunner
Feb 20, 2018·Molecular Cancer·Simar Pal SinghRudi W Hendriks
Mar 9, 2018·American Journal of Physiology. Lung Cellular and Molecular Physiology·Jon M FlorenceAnna K Kurdowska
Apr 10, 2018·European Journal of Medicinal Chemistry·Chengyuan LiangSuresh Thareja
Mar 20, 2019·Expert Opinion on Therapeutic Patents·Yifan FengMinhang Xin
Apr 17, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Philipp HaselmayerRoland Grenningloh
May 11, 2019·The New England Journal of Medicine·Xavier MontalbanUNKNOWN Evobrutinib Phase 2 Study Group
Jun 6, 2019·Nature Reviews. Rheumatology·Grainne Murphy, David A Isenberg

❮ Previous
Next ❯

Citations

May 2, 2021·Bioorganic & Medicinal Chemistry·Hui QiuBrian Sherer
Jul 25, 2021·International Journal of Molecular Sciences·Chiara BrulloAndrea Spallarossa
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Datong ZhangFancui Meng
Oct 1, 2021·Journal of Medicinal Chemistry·Murugaiah A M Subbaiah, Nicholas A Meanwell

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.