1SVH

Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8

Summary for 1SVH

• Entry DOI: 10.2210/pdb1svh/pdb
• Related: 1SVE 1SVG 1VEB
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, cAMP-dependent protein kinase inhibitor, alpha form, (3R,4S)-N-(4-{TRANS-2-[4-(2-FLUORO-6-HYDROXY-3-METHOXY-BENZOYL)-PHENYL]-VINYL}-AZEPAN-3-YL)-ISONICOTINAMIDE, ... (4 entities in total)
• Functional Keywords: kinase-inhibitor-complex, serine/threonine-protein kinase, balanol derivative, transferase
• Biological source: Bos taurus (cattle); More
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43422.37

Authors

Breitenlechner, C.B.,Wegge, T.,Berillon, L.,Graul, K.,Marzenell, K.,Friebe, W.G.,Thomas, U.,Schumacher, R.,Huber, R.,Engh, R.A.,Masjost, B. (deposition date: 2004-03-29, release date: 2005-03-29, Last modification date: 2024-10-16)

Primary citation

Breitenlechner, C.B.,Wegge, T.,Berillon, L.,Graul, K.,Marzenell, K.,Friebe, W.G.,Thomas, U.,Schumacher, R.,Huber, R.,Engh, R.A.,Masjost, B.
Structure-based optimization of novel azepane derivatives as PKB inhibitors
J.Med.Chem., 47:1375-1390, 2004

PubMed Abstract: Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)amino]-azepan-4-yl ester (1) (IC(50) (PKB-alpha) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl]-isonicotinamide (4), (3R,4R)-N-[4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl]-isonicotinamide (5), N-[(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl]-azepan-3-yl)-isonicotinamide (6), N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl]-isonicotinamide (7), and N-[(3R,4S)-4-(4-[trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl]-vinyl]-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1) Compound 4 was found to be plasma stable and highly active (IC(50) (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.

PubMed: 14998327
DOI: 10.1021/jm0310479

Experimental method

X-RAY DIFFRACTION (2.3 Å)