1. Academic Validation
  2. Design of Potent and Selective Covalent Inhibitors of Bruton's Tyrosine Kinase Targeting an Inactive Conformation

Design of Potent and Selective Covalent Inhibitors of Bruton's Tyrosine Kinase Targeting an Inactive Conformation

  • ACS Med Chem Lett. 2019 Sep 6;10(10):1467-1472. doi: 10.1021/acsmedchemlett.9b00317.
Robert Pulz 1 Daniela Angst 1 Janet Dawson 1 Francois Gessier 1 Sascha Gutmann 1 Rene Hersperger 1 Alexandra Hinniger 1 Philipp Janser 1 Guido Koch 1 Laszlo Revesz 1 Anna Vulpetti 1 Rudolf Waelchli 1 Alfred Zimmerlin 1 Bruno Cenni 1
Affiliations

Affiliation

  • 1 Global Discovery Chemistry, Autoimmunity, Transplantation & Inflammation, Chemical Biology & Therapeutics, and PK Sciences, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.
Abstract

Bruton's tyrosine kinase (Btk) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A Btk Inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent Btk inhibitors. Starting from the selective reversible inhibitor 3 binding to an inactive conformation of Btk, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 4 covalently modified Btk and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic stability resulted in compounds such as 8, which maintained the excellent kinase selectivity and showed improved Btk occupancy in vivo.

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