2UZU

PKA structures of indazole-pyridine series of AKT inhibitors

Summary for 2UZU

• Entry DOI: 10.2210/pdb2uzu/pdb
• Related: 1KMU 1KMW 1Q24 1Q61 1Q62 1Q8T 1Q8U 1Q8W 1SMH 1STC 1SVE 1SVG 1SVH 1SZM 1VEB 1XH4 1XH5 1XH6 1XH7 1XH8 1XH9 1XHA 1YDR 1YDS 1YDT 2C1A 2C1B 2F7E 2GFC 2GNF 2GNG 2GNH 2GNI 2GNJ 2GNL 2JDS 2JDT 2JDV 2UVX 2UVY 2UVZ 2UW0 2UW3 2UW4 2UW5 2UW6 2UW7 2UW8 2UZT 2UZV 2UZW
• Descriptor: CAMP-DEPENDENT PROTEIN KINASE, ALPHA-CATALYTIC SUBUNIT, CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA, (2S)-1-(1H-INDOL-3-YL)-3-{[5-(3-METHYL-1H-INDAZOL-5-YL)PYRIDIN-3-YL]OXY}PROPAN-2-AMINE (3 entities in total)
• Functional Keywords: camp, kinase, myristate, transferase, lipoprotein, serine/threonine-protein kinase, phosphorylation, protein kinase a, nucleotide-binding, protein kinase inhibitor, atp- binding, akt inhibitors, nuclear protein
• Biological source: BOS TAURUS (BOVINE); More
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 41839.94

Authors

Zhu, G.D.,Gandhi, V.B.,Gong, J.,Thomas, S.,Woods, K.W.,Song, X.,Li, T.,Diebold, R.B.,Luo, Y.,Liu, X.,Guan, R.,Klinghofer, V.,Johnson, E.F.,Bouska, J.,Olson, A.,Marsh, K.C.,Stoll, V.S.,Mamo, M.,Polakowski, J.,Campbell, T.J.,Penning, T.D.,Li, Q.,Rosenberg, S.H.,Giranda, V.L. (deposition date: 2007-05-01, release date: 2007-06-05, Last modification date: 2024-05-08)

Primary citation

Zhu, G.D.,Gandhi, V.B.,Gong, J.,Thomas, S.,Woods, K.W.,Song, X.,Li, T.,Diebold, R.B.,Luo, Y.,Liu, X.,Guan, R.,Klinghofer, V.,Johnson, E.F.,Bouska, J.,Olson, A.,Marsh, K.C.,Stoll, V.S.,Mamo, M.,Polakowski, J.,Campbell, T.J.,Martin, R.L.,Gintant, G.A.,Penning, T.D.,Li, Q.,Rosenberg, S.H.,Giranda, V.L.
Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension.
J.Med.Chem., 50:2990-, 2007

PubMed Abstract: Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

PubMed: 17523610
DOI: 10.1021/JM0701019

Experimental method

X-RAY DIFFRACTION (2.4 Å)