6NZM

Brutons tyrosine kinase in complex with compound 50.

Summary for 6NZM

• Entry DOI: 10.2210/pdb6nzm/pdb
• Descriptor: Tyrosine-protein kinase BTK, N-[2-fluoro-6-(pyrrolidin-1-yl)phenyl]-N'-{3-[(2R)-1-(2-hydroxyethyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-2-yl]phenyl}urea, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: brutons tyrosine kinase btk, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 66039.67

Authors

Marcotte, D.J. (deposition date: 2019-02-14, release date: 2019-06-12, Last modification date: 2024-03-13)

Primary citation

Hopkins, B.T.,Bame, E.,Bell, N.,Bohnert, T.,Bowden-Verhoek, J.K.,Bui, M.,Cancilla, M.T.,Conlon, P.,Cullen, P.,Erlanson, D.A.,Fan, J.,Fuchs-Knotts, T.,Hansen, S.,Heumann, S.,Jenkins, T.J.,Marcotte, D.,McDowell, B.,Mertsching, E.,Negrou, E.,Otipoby, K.L.,Poreci, U.,Romanowski, M.J.,Scott, D.,Silvian, L.,Yang, W.,Zhong, M.
Optimization of novel reversible Bruton's tyrosine kinase inhibitors identified using Tethering-fragment-based screens.
Bioorg.Med.Chem., 27:2905-2913, 2019

PubMed Abstract: Since the approval of ibrutinib for the treatment of B-cell malignancies in 2012, numerous clinical trials have been reported using covalent inhibitors to target Bruton's tyrosine kinase (BTK) for oncology indications. However, a formidable challenge for the pharmaceutical industry has been the identification of reversible, selective, potent molecules for inhibition of BTK. Herein, we report application of Tethering-fragment-based screens to identify low molecular weight fragments which were further optimized to improve on-target potency and ADME properties leading to the discovery of reversible, selective, potent BTK inhibitors suitable for pre-clinical proof-of-concept studies.

PubMed: 31138459
DOI: 10.1016/j.bmc.2019.05.021

Experimental method

X-RAY DIFFRACTION (1.72 Å)