2OJF

Crystal structure of Protein Kinase A in complex with Pyridine-Pyrazolopyridine based inhibitors

Summary for 2OJF

• Entry DOI: 10.2210/pdb2ojf/pdb
• Related: 1OH0
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, Inhibitory peptide, (2S)-1-(6H-INDOL-3-YL)-3-{[5-(7H-PYRAZOLO[3,4-C]PYRIDIN-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE (3 entities in total)
• Functional Keywords: protein kinase a, akt, transferase
• Biological source: Bos taurus (cattle)
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43288.50

Authors

Stoll, V.S. (deposition date: 2007-01-12, release date: 2007-03-20, Last modification date: 2023-12-27)

Primary citation

Zhu, G.D.,Gong, J.,Gandhi, V.B.,Woods, K.,Luo, Y.,Liu, X.,Guan, R.,Klinghofer, V.,Johnson, E.F.,Stoll, V.S.,Mamo, M.,Li, Q.,Rosenberg, S.H.,Giranda, V.L.
Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt.
Bioorg.Med.Chem., 15:2441-2452, 2007

PubMed Abstract: Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.

PubMed: 17258463
DOI: 10.1016/j.bmc.2007.01.010

Experimental method

X-RAY DIFFRACTION (2.1 Å)