PDBsum entry 2uzt

Transferase

PDB id: 2uzt

Contents

Protein chains

336 a.a. *

20 a.a. *

Ligands

SS3

* Residue conservation analysis

PDB id:

2uzt

Name:

Transferase

Title:

Pka structures of akt, indazole-pyridine inhibitors

Structure:

Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Fragment: residues 15-350. Synonym: pka c-alpha, protein kinase a. Engineered: yes. Camp-dependent protein kinase inhibitor alpha. Chain: b. Fragment: residues 5-24. Synonym: pki-alpha, inibitory peptide.

Source:

Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9913

Resolution:

2.10Å R-factor: 0.273 R-free: 0.313

Authors:

G.D.Zhu,V.B.Gandhi,J.Gong,S.Thomas,K.W.Woods,X.Song,T.Li,R.B.Diebold, Y.Luo,X.Liu,R.Guan,V.Klinghofer,E.F.Johnson,J.Bouska,A.Olson, K.C.Marsh,V.S.Stoll,M.Mamo,J.Polakowski,T.J.Campbell,T.D.Penning, Q.Li,S.H.Rosenberg,V.L.Giranda

Key ref:

G.D.Zhu et al. (2007). Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J Med Chem, 50, 2990-3003. PubMed id: 17523610

Date:

01-May-07 Release date: 05-Jun-07

Protein chain

P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus

Seq: 351 a.a.

Struc: 336 a.a.*

Protein chain

Q3SX13  (IPKA_BOVIN) -  cAMP-dependent protein kinase inhibitor alpha from Bos taurus

Seq: 76 a.a.

Struc: 20 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.11.11 - cAMP-dependent protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 3: Chain B: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

J Med Chem 50:2990-3003 (2007)

PubMed id: 17523610

Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.

G.D.Zhu, V.B.Gandhi, J.Gong, S.Thomas, K.W.Woods, X.Song, T.Li, R.B.Diebold, Y.Luo, X.Liu, R.Guan, V.Klinghofer, E.F.Johnson, J.Bouska, A.Olson, K.C.Marsh, V.S.Stoll, M.Mamo, J.Polakowski, T.J.Campbell, R.L.Martin, G.A.Gintant, T.D.Penning, Q.Li, S.H.Rosenberg, V.L.Giranda.

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.