5TIU

Crystal structure of SYK kinase domain with inhibitor

Summary for 5TIU

• Entry DOI: 10.2210/pdb5tiu/pdb
• Descriptor: Tyrosine-protein kinase SYK, 5-{[(2S)-2-aminopropyl]amino}-3-(1H-indol-2-yl)pyrazine-2-carboxamide (3 entities in total)
• Functional Keywords: carboxamide spleen tyrosine kinase (syk), transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane : P43405
• Total number of polymer chains: 1
• Total formula weight: 34194.36

Authors

Ellis, J.M.,Altman, M.D.,Cash, B.,Haidle, A.M.,Kubiak, R.L.,Maddess, M.L.,Yan, Y.,Northrup, A.B. (deposition date: 2016-10-03, release date: 2017-01-11, Last modification date: 2024-04-03)

Primary citation

Ellis, J.M.,Altman, M.D.,Cash, B.,Haidle, A.M.,Kubiak, R.L.,Maddess, M.L.,Yan, Y.,Northrup, A.B.
Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.
ACS Med Chem Lett, 7:1151-1155, 2016

PubMed Abstract: Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a strain.

PubMed: 27994755
DOI: 10.1021/acsmedchemlett.6b00353

Experimental method

X-RAY DIFFRACTION (1.49 Å)