Tuesday, February 25, 2020

Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase

Daniela AngstFrançois GessierPhilipp JanserAnna VulpettiRudolf WälchliChristian BeerliAmanda Littlewood-EvansJanet DawsonBarbara Nuesslein-HildesheimGrazyna WieczorekSascha GutmannClemens ScheuflerAlexandra HinnigerAlfred Gilbert ZimmerlinEnrico G. FunhoffRobert Pulz, and Bruno Cenni

J. Med. Chem. 2020

Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, 25), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent in vivo target occupancy with an EC90 of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in Phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren’s Syndrome.

Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry

Roman C. Sarott, Inchul You, Yen-Der Li, Sean T. Toenjes, Katherine A. Donovan, Pooreum Seo, Martha Ordonez, Woong Sub Byun, Muhammad Murtaz...