9Y5B

Co-crystal structure of BTK kinase domain with non-covalent inhibitor

This is a non-PDB format compatible entry.

Summary for 9Y5B

• Entry DOI: 10.2210/pdb9y5b/pdb
• Descriptor: Tyrosine-protein kinase BTK, 1-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-4-[4-(piperidin-4-yl)anilino]-1H-pyrazole-5-carboxamide (3 entities in total)
• Functional Keywords: btk, bruton's tyrosin kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32811.62

Authors

Sangwoo, C.,Nathan, M.,Xinlin, D. (deposition date: 2025-09-04, release date: 2026-07-15)

Primary citation

Liu, G.,Liu, S.,Cho, S.,Chae, H.D.,Zhou, W.,Zhang, L.,Khanna, A.,Zeng, X.,Du, X.,Zhu, H.,Chang, T.P.,Max, N.,Kumar, M.,Chen, C.,Lee, L.
Strategic Use of Benzylic Alcohols Reveals Cryptic Hydrogen-Bonding Interactions: Discovery of HBC-12551 as a Potent Noncovalent Bruton's Tyrosine Kinase Inhibitor.
J.Med.Chem., 69:2867-2887, 2026

PubMed Abstract: 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 , 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.

PubMed: 41616212
DOI: 10.1021/acs.jmedchem.5c02785

Experimental method

X-RAY DIFFRACTION (1.904 Å)