The electron density map corresponding to zanubrutinib and Cys481 showed covalent linkage with Cys481. Zanubrutinib forms three critical hydrogen bonds with hinge residues Glu475 and Met477. Compared with the co-crystal structure of ibrutinib with BTK, there is an additional hydrogen bond between the backbone carbonyl oxygen of Met477 and the 4-NH. The terminal phenyl group engages in a T-shape π–π stacking with Phe540, and the pyrazolyl nitrogen interacts with Lys430 via a water bridge. The warhead carbonyl also interacts indirectly with the amide NH of Asn484 via two water molecules. Both zanubrutinib and ibrutinib have a piperidinyl linker; however, they adopt two different binding modes in complex with BTK. In addition, a single crystal X-ray structure of zanubrutinib showed a classic intramolecular H-bond between carboxamide oxygen and the 4-NH, which confirmed the bioisosteric mimicry of the aminopyrimidine ring.
Zanubrutinib, a second-generation BTK inhibitor discovered and developed by BeiGene in China, has been approved by the FDA (in 2019) for treating chronic lymphocytic leukemia (CLL) and certain other indications. Zanubrutinib has lower toxicity and better efficacy than ibrutinib. It is in direct competition with AstraZeneca’s acalabrutinib for the $12 billion blood cancer market currently dominated by the first-in-class BTK inhibitor ibrutinib.
Zanubrutinib (BGB-3111) is a highly selective second-generation irreversible BTK inhibitor discovered by BeiGene company, which was approved by U.S. FDA in 2019 with a Brukinsa trade name. In preclinical animal experiments, Zanubrutinib showed good oral bioavailability, higher plasma exposure and more complete target inhibition than Ibrutinib in tissues. Compared with Ibrutinib, Zanubrutinib showed more specific, long-lasting selectivity, fewer off-targets and fewer adverse reactions. It only occasionally causes atrial fibrillation or bleeding events. On January 14, 2019, Zanubrutinib capsules were approved by U.S. FDA for a breaking through treatment certification. In mid-November of the same year, Zanubrutinib capsules were approved for marketing in the United States for the treatment of adult mantle cell lymphoma patients who have received at least one of the previous therapies.
Zanubrutinib is classified as a Bruton''s tyrosine kinase inhibitor. Zanubrutinib is a medication for the treatment of adults with mantle cell lymphoma.
Class: non-receptor tyrosine kinase
Treatment: MCL, MZL, WM
Oral bioavailability = 15%
Elimination half-life = 3.3 h
Protein binding = 94%
Zanubrutinib showed a mean terminal elimination half-life of approximately 2–4 h (160 or 320 mg, QD) and an estimated oral bioavailability of 15%, relative to 3.9% (fasting state) for ibrutinib. Zanubrutinib is primarily eliminated hepatically via CYP3A4, but its metabolites have not been characterized.
