5T18

Crystal structure of Bruton agammabulinemia tyrosine kinase complexed with BMS-986142 aka (2s)-6-fluoro-5-[3-(8-fluoro-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)-2-methylphenyl]-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1h-carbazole-8-carboxamide

Summary for 5T18

• Entry DOI: 10.2210/pdb5t18/pdb
• Descriptor: Tyrosine-protein kinase BTK, 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (3 entities in total)
• Functional Keywords: kinase, btk, atk, xla, psctk1, agmx1, at, imd1, mgc126261, mgc126262 bpk, ----, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 1
• Total formula weight: 31776.51

Authors

Muckelbauer, J.K. (deposition date: 2016-08-18, release date: 2017-03-08, Last modification date: 2024-03-06)

Primary citation

Watterson, S.H.,De Lucca, G.V.,Shi, Q.,Langevine, C.M.,Liu, Q.,Batt, D.G.,Beaudoin Bertrand, M.,Gong, H.,Dai, J.,Yip, S.,Li, P.,Sun, D.,Wu, D.R.,Wang, C.,Zhang, Y.,Traeger, S.C.,Pattoli, M.A.,Skala, S.,Cheng, L.,Obermeier, M.T.,Vickery, R.,Discenza, L.N.,D'Arienzo, C.J.,Zhang, Y.,Heimrich, E.,Gillooly, K.M.,Taylor, T.L.,Pulicicchio, C.,McIntyre, K.W.,Galella, M.A.,Tebben, A.J.,Muckelbauer, J.K.,Chang, C.,Rampulla, R.,Mathur, A.,Salter-Cid, L.,Barrish, J.C.,Carter, P.H.,Fura, A.,Burke, J.R.,Tino, J.A.
Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers.
J. Med. Chem., 59:9173-9200, 2016

PubMed Abstract: Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.

PubMed: 27583770
DOI: 10.1021/acs.jmedchem.6b01088

Experimental method

X-RAY DIFFRACTION (1.5 Å)