PDBsum entry 5lmb

Transferase

PDB id

5lmb

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Contents

			Protein chains

					265 a.a.

			Ligands

					6ZF ×2


					GOL ×7

			Waters ×394

PDB id:

5lmb

Links

Name:

Transferase

Title:

Human spleen tyrosine kinase kinase domain in complex with azanaphthyridine inhibitor

Structure:

Tyrosine-protein kinase syk. Chain: a, b. Fragment: unp residues 360-635. Synonym: spleen tyrosine kinase,p72-syk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: syk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.95Å

R-factor:

0.178

R-free:

0.228

Authors:

D.O.Somers,M.Neu

Key ref:

N.S.Garton et al. (2016). Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors. Bioorg Med Chem Lett, 26, 4606-4612. PubMed id: 27578246 DOI: 10.1016/j.bmcl.2016.08.070

Date:

29-Jul-16

Release date:

14-Sep-16

PROCHECK

	Headers

	References

Protein chains

P43405 (KSYK_HUMAN) - Tyrosine-protein kinase SYK from Homo sapiens

Seq: Struc:

Seq: Struc:					635 a.a. 265 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.2.7.10.2 - non-specific protein-tyrosine kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein]	+	ATP	=	O-phospho-L-tyrosyl-[protein]	+	ADP	+	H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.bmcl.2016.08.070	Bioorg Med Chem Lett 26:4606-4612 (2016)
PubMed id: 27578246

Optimisation of a novel series of potent and orally bioavailable azanaphthyridine SYK inhibitors.
N.S.Garton, M.D.Barker, R.P.Davis, C.Douault, E.Hooper-Greenhill, E.Jones, H.D.Lewis, J.Liddle, D.Lugo, S.McCleary, A.G.S.Preston, C.Ramirez-Molina, M.Neu, T.J.Shipley, D.O.Somers, R.J.Watson, D.M.Wilson.

ABSTRACT

The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the pKa. Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay.