Richard Caldwell, Hui Qiu, Ben C Askew, Andrew T Bender, Nadia Brugger, Montserrat Camps, Mohanraj Dhanabal, Vikram Dutt, Thomas Eichhorn, Anna S Gardberg, Andreas Goutopoulos, Roland Grenningloh, Jared Head, Brian Healey, Brian L Hodous, Bayard R Huck, Theresa L Johnson, Christopher Jones, Reinaldo C Jones, Igor Mochalkin, Federica Morandi, Ngan Nguyen, Michael Meyring, Justin R Potnick, Dusica Cvetinovic Santos, Ralf Schmidt, Brian Sherer, Adam Shutes, Klaus Urbahns, Ariele Viacava Follis, Ansgar A Wegener, Simone C. Zimmerli, and Lesley Liu-Bujalski
J. Med. Chem., 2019
DOI: 10.1021/acs.jmedchem.9b00794
Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity) which preclude their evaluation in non-oncology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over
epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
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