Fig. 3

The structural diagram of Bruton tyrosine kinase (BTK). The BTK protein is a 77 kDa protein of 659 amino acids, which contains five different protein interaction domains. There are two critical tyrosine phosphorylation sites, Y223 in the SH3 domain and Y551 in the kinase domain. BTK inhibitors bind to the BTK kinase domain and blocks the catalytic activity of BTK. Currently available covalent BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, and orelabrutinib, selectively bind to C481 residue in the allosteric inhibitory segment of the BTK kinase domain. The non-covalent BTK inhibitors do not bind to C481. For example, ARQ 531 binds to BTK by forming hydrogen bonds with E475 and Y476 residues [56]. Fenebrutinib forms hydrogen bonds with K430, M477, and D539 residues [50]