2XH5

Structure of 4-(4-tert-Butylbenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4- yl)piperidin-4-amine bound to PKB

Replaces:  2X37

Summary for 2XH5

• Entry DOI: 10.2210/pdb2xh5/pdb
• Related: 1GNG 1GZK 1GZN 1GZO 1H8F 1I09 1J1B 1J1C 1MRV 1MRY 1O6K 1O6L 1O9U 1P6S 1PYX 1Q3D 1Q3W 1Q41 1Q4L 1Q5K 1R0E 1UV5 2JDO 2JDR 2JLD 2UW9 2X39
• Descriptor: RAC-BETA SERINE/THREONINE-PROTEIN KINASE, GLYCOGEN SYNTHASE KINASE-3 BETA, 4-(4-tert-butylbenzyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-aminium, ... (4 entities in total)
• Functional Keywords: serine/threonine-protein kinase, nucleotide-binding, wnt signaling pathway, kinase, transferase, phosphoprotein
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 41348.11

Authors

Davies, T.G.,McHardy, T.,Caldwell, J.J.,Cheung, K.M.,Hunter, L.J.,Taylor, K.,Rowlands, M.,Ruddle, R.,Henley, A.,Brandon, A.D.,Valenti, M.,Fazal, L.,Seavers, L.,Raynaud, F.I.,Eccles, S.A.,Aherne, G.W.,Garrett, M.D.,Collins, I. (deposition date: 2010-06-09, release date: 2010-06-16, Last modification date: 2024-10-16)

Primary citation

Mchardy, T.,Caldwell, J.J.,Cheung, K.M.,Hunter, L.J.,Taylor, K.,Rowlands, M.,Ruddle, R.,Henley, A.,De Haven Brandon, A.,Valenti, M.,Davies, T.G.,Fazal, L.,Seavers, L.,Raynaud, F.I.,Eccles, S.A.,Aherne, G.W.,Garrett, M.D.,Collins, I.
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-, 2010

PubMed 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.

PubMed: 20151677
DOI: 10.1021/JM901788J

Experimental method

X-RAY DIFFRACTION (2.72 Å)