8FF0
Structure of BTK kinase domain with the second-generation inhibitor tirabrutinib
Summary for 8FF0
| Entry DOI | 10.2210/pdb8ff0/pdb |
| Related | 8FD9 |
| Descriptor | Tyrosine-protein kinase BTK, 6-azanyl-9-[(3~{R})-1-[(~{E})-but-2-enoyl]pyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one (3 entities in total) |
| Functional Keywords | inhibitor, kinase, complex, covalent, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 32278.02 |
| Authors | Lin, D.Y.,Andreotti, A.H. (deposition date: 2022-12-07, release date: 2023-07-05, Last modification date: 2024-11-20) |
| Primary citation | Lin, D.Y.,Andreotti, A.H. Structure of BTK kinase domain with the second-generation inhibitors acalabrutinib and tirabrutinib. Plos One, 18:e0290872-e0290872, 2023 Cited by PubMed Abstract: Bruton's tyrosine kinase (BTK) is the target of the therapeutic agent, Ibrutinib, that treats chronic lymphocyte leukemia (CLL), mantle cell lymphoma (MCL) and other B cell malignancies. Ibrutinib is a first in class, covalent BTK inhibitor that limits B-cell survival and proliferation. Designing new inhibitors of BTK has been an important objective for advancing development of improved therapeutic agents against cancer and autoimmune disorders. Based on the success of Ibrutinib, several second-generation irreversible BTK inhibitors have been developed that exhibit fewer off-target effects. However, the binding-mode and their interaction with Btk have not been experimentally determined and evaluated at atomic resolution. Here we determined the first crystal structure of the BTK kinase domain in complex with acalabrutinib. In addition, we report a structure of the BTK/tirabrutinib complex and compare these structures with previously solved structures. The structures provide insight in the superior selectivity reported for acalabrutinb and guide future BTK inhibitor development. PubMed: 37651403DOI: 10.1371/journal.pone.0290872 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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