Medicinal Chemistry Strategies for the Development of Bruton’s Tyrosine Kinase Inhibitors against Resistance

Despite significant efficacy, one
of the major limitations of small-molecule
Bruton’s tyrosine kinase (BTK) agents is the presence of clinically
acquired resistance, which remains a major clinical challenge. This
Perspective focuses on medicinal chemistry strategies for the development
of BTK small-molecule inhibitors against resistance, including the
structure-based design of BTK inhibitors targeting point mutations,
e.g., (i) developing noncovalent inhibitors from covalent inhibitors,
(ii) avoiding steric hindrance from mutated residues, (iii) making
interactions with the mutated residue, (iv) modifying the solvent-accessible
region, and (v) developing new scaffolds. Additionally, a comparative
analysis of multi-inhibitions of BTK is presented based on cross-comparisons
between 2916 unique BTK ligands and 283 other kinases that cover 7108
dual/multiple inhibitions. Finally, targeting the BTK allosteric site
and uding proteolysis-targeting chimera (PROTAC) as two potential
strategies are addressed briefly, while also illustrating the possibilities
and challenges to find novel ligands of BTK.