6DI9
CRYSTAL STRUCTURE OF BTK IN COMPLEX WITH COVALENT INHIBITOR
Summary for 6DI9
| Entry DOI | 10.2210/pdb6di9/pdb |
| Related | 6di0 6di3 6di5 |
| Descriptor | Tyrosine-protein kinase BTK, 6-[(3S)-3-(acryloylamino)pyrrolidin-1-yl]-2-{[4-(tert-butylcarbamoyl)phenyl]amino}pyridine-3-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total) |
| Functional Keywords | lead optimization, fragment screening by x-ray, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32126.95 |
| Authors | |
| Primary citation | Qiu, H.,Liu-Bujalski, L.,Caldwell, R.D.,Follis, A.V.,Gardberg, A.,Goutopoulos, A.,Grenningloh, R.,Head, J.,Johnson, T.,Jones, R.,Mochalkin, I.,Morandi, F.,Neagu, C.,Sherer, B. Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit. Bioorg. Med. Chem. Lett., 28:2939-2944, 2018 Cited by PubMed Abstract: Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR. PubMed: 30122225DOI: 10.1016/j.bmcl.2018.07.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
Download full validation report
