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.
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. 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.
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