Strategic Use of Benzylic Alcohols Reveals Cryptic Hydrogen-Bonding Interactions: Discovery of HBC-12551 as a Potent Noncovalent Bruton’s Tyrosine Kinase Inhibitor

Bruton’s tyrosine kinase (BTK) represents a key
therapeutic
target for B-cell malignancies. While covalent inhibitors have shown
efficacy, the emergence of resistant BTK mutants necessitates the
development of noncovalent alternatives with improved selectivity
and tolerability profiles. Utilizing structure-based drug design,
we identified HBC-12551, a novel noncovalent BTK inhibitor. By strategically
incorporating a hydrogen-bonding interaction with the backbone NH
of Cys481, HBC-12551 demonstrated significantly enhanced potency.
This compound potently inhibited both wild-type and C481S mutant BTK
and exhibited robust antiproliferative effects in B-cell lymphoma
cell lines. Preclinical studies further revealed promising antitumor
activity in vivo, coupled with favorable pharmacokinetic
properties. These findings suggest that HBC-12551 holds significant
potential as a promising therapeutic candidate for the treatment of
B-cell malignancies.