7LTY

Bruton's tyrosine kinase in complex with compound 23

Summary for 7LTY

• Entry DOI: 10.2210/pdb7lty/pdb
• Related: 6W07
• Descriptor: Isoform BTK-C of Tyrosine-protein kinase BTK, ~{N}-[(5~{R})-2-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]-6,7,8,9-tetrahydro-5~{H}-benzo[7]annulen-5-yl]-3-propan-2-yloxy-azetidine-1-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: transferase, transferase inhibitor, kinase, kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31761.57

Authors

Metrick, C.M.,Marcotte, D.J. (deposition date: 2021-02-20, release date: 2022-01-12, Last modification date: 2023-10-18)

Primary citation

Hopkins, B.T.,Bame, E.,Bajrami, B.,Black, C.,Bohnert, T.,Boiselle, C.,Burdette, D.,Burns, J.C.,Delva, L.,Donaldson, D.,Grater, R.,Gu, C.,Hoemberger, M.,Johnson, J.,Kapadnis, S.,King, K.,Lulla, M.,Ma, B.,Marx, I.,Magee, T.,Meissner, R.,Metrick, C.M.,Mingueneau, M.,Murugan, P.,Otipoby, K.L.,Polack, E.,Poreci, U.,Prince, R.,Roach, A.M.,Rowbottom, C.,Santoro, J.C.,Schroeder, P.,Tang, H.,Tien, E.,Zhang, F.,Lyssikatos, J.
Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis.
J.Med.Chem., 65:1206-1224, 2022

PubMed Abstract: Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

PubMed: 34734694
DOI: 10.1021/acs.jmedchem.1c00926

Experimental method

X-RAY DIFFRACTION (1.69 Å)