PDBsum entry 2x39

Transferase

PDB id: 2x39

Contents

Protein chain

317 a.a. *

Ligands

GLY-ARG-PRO-ARG-THR-THR-SER-PHE-ALA-GLU

X39

Waters ×246

* Residue conservation analysis

PDB id:

2x39

Name:

Transferase

Title:

Structure of 4-amino-n-(4-chlorobenzyl)-1-(7h-pyrrolo(2,3-d)pyrimidin- 4-yl)piperidine-4-carboxamide bound to pkb

Structure:

Rac-beta serine/threonine-protein kinase. Chain: a. Fragment: kinase catalytic domain, residues 146-467. Synonym: rac-pk-beta, protein kinase akt-2, protein kinase b\,beta, pkb beta. Engineered: yes. Other_details: piftide sequence (eeqemfedfdyiadw) replaces natural pkb sequence after residue 464c. Glycogen synthase kinase-3 beta.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.93Å R-factor: 0.169 R-free: 0.226

Authors:

T.G.Davies,T.Mchardy,J.J.Caldwell,K.M.Cheung,L.J.Hunter,K.Taylor, M.Rowlands,R.Ruddle,A.Henley,A.D.Brandon,M.Valenti,L.Fazal, L.Seavers,F.I.Raynaud,S.A.Eccles,G.W.Aherne,M.D.Garrett,I.Collins

Key ref:

T.McHardy et al. (2010). Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J Med Chem, 53, 2239-2249. PubMed id: 20151677

Date:

22-Jan-10 Release date: 23-Feb-10

Protein chain

P31751  (AKT2_HUMAN) -  RAC-beta serine/threonine-protein kinase from Homo sapiens

Seq: 481 a.a.

Struc: 317 a.a.*

* PDB and UniProt seqs differ at 13 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine 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⁺

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

reference

J Med Chem 53:2239-2249 (2010)

PubMed id: 20151677

Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).

T.McHardy, J.J.Caldwell, K.M.Cheung, L.J.Hunter, K.Taylor, M.Rowlands, R.Ruddle, A.Henley, A.de Haven Brandon, M.Valenti, T.G.Davies, L.Fazal, L.Seavers, F.I.Raynaud, S.A.Eccles, G.W.Aherne, M.D.Garrett, I.Collins.

ABSTRACT

Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.