6S90

BTK in complex with an inhibitor

Summary for 6S90

• Entry DOI: 10.2210/pdb6s90/pdb
• Descriptor: Tyrosine-protein kinase BTK, 4-~{tert}-butyl-~{N}-[2-methyl-3-[6-[4-(4-methylpiperazin-1-yl)carbonylphenyl]-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide (3 entities in total)
• Functional Keywords: btk, bruton tyrosine kinase, agammaglobulinaemia tyrosine kinase, atk, b-cell progenitor kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63415.01

Authors

Gutmann, S.,Hinniger, A. (deposition date: 2019-07-11, release date: 2019-09-18, Last modification date: 2024-05-15)

Primary citation

Pulz, R.,Angst, D.,Dawson, J.,Gessier, F.,Gutmann, S.,Hersperger, R.,Hinniger, A.,Janser, P.,Koch, G.,Revesz, L.,Vulpetti, A.,Waelchli, R.,Zimmerlin, A.,Cenni, B.
Design of Potent and Selective Covalent Inhibitors of Bruton's Tyrosine Kinase Targeting an Inactive Conformation.
Acs Med.Chem.Lett., 10:1467-1472, 2019

PubMed 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 binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 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 . Optimization of whole blood potency and metabolic stability resulted in compounds such as , which maintained the excellent kinase selectivity and showed improved BTK occupancy .

PubMed: 31620235
DOI: 10.1021/acsmedchemlett.9b00317

Experimental method

X-RAY DIFFRACTION (1.82 Å)