Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors

• Main Authors: Rula Zain, Mauno Vihinen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-07-01
• Series: Frontiers in Immunology
• Subjects: BTK inhibitors; ibrutinib; acalabrutinib; zanubrutinib; fenebrutinib; protein-inhibitor interactions
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2021.694853/full

Low-molecular weight chemical compounds have a longstanding history as drugs. Target specificity and binding efficiency represent major obstacles for small molecules to become clinically relevant. Protein kinases are attractive cellular targets; however, they are challenging because they present one of the largest protein families and share structural similarities. Bruton tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, has received much attention as a promising target for the treatment of B-cell malignancies and more recently autoimmune and inflammatory diseases. Here we describe the structural properties and binding modes of small-molecule BTK inhibitors, including irreversible and reversible inhibitors. Covalently binding compounds, such as ibrutinib, acalabrutinib and zanubrutinib, are discussed along with non-covalent inhibitors fenebrutinib and RN486. The focus of this review is on structure-function relationships.