6OMU
Structure of human Bruton's Tyrosine Kinase in complex with Evobrutinib
Summary for 6OMU
| Entry DOI | 10.2210/pdb6omu/pdb |
| Descriptor | Tyrosine-protein kinase BTK, CHLORIDE ION, 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one, ... (4 entities in total) |
| Functional Keywords | kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32063.25 |
| Authors | Mochalkin, I.,Gardberg, A.S. (deposition date: 2019-04-19, release date: 2019-08-14, Last modification date: 2023-10-11) |
| Primary citation | Caldwell, R.D.,Qiu, H.,Askew, B.C.,Bender, A.T.,Brugger, N.,Camps, M.,Dhanabal, M.,Dutt, V.,Eichhorn, T.,Gardberg, A.S.,Goutopoulos, A.,Grenningloh, R.,Head, J.,Healey, B.,Hodous, B.L.,Huck, B.R.,Johnson, T.L.,Jones, C.,Jones, R.C.,Mochalkin, I.,Morandi, F.,Nguyen, N.,Meyring, M.,Potnick, J.R.,Santos, D.C.,Schmidt, R.,Sherer, B.,Shutes, A.,Urbahns, K.,Follis, A.V.,Wegener, A.A.,Zimmerli, S.C.,Liu-Bujalski, L. Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases. J.Med.Chem., 62:7643-7655, 2019 Cited by PubMed Abstract: Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. PubMed: 31368705DOI: 10.1021/acs.jmedchem.9b00794 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.41 Å) |
Structure validation
Download full validation report
