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.