3OW4

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors

Summary for 3OW4

• Entry DOI: 10.2210/pdb3ow4/pdb
• Related: 3OW3
• Descriptor: RAC-alpha serine/threonine-protein kinase, GSK 3 beta peptide, (2R)-3-(1H-indol-3-yl)-1-{4-[(5S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-1-oxopropan-2-amine, ... (4 entities in total)
• Functional Keywords: serine-threonine kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P31749
• Total number of polymer chains: 4
• Total formula weight: 82025.47

Authors

Dizon, F.,Wu, W.,Vigers, G.P.A.,Brandhuber, B.J. (deposition date: 2010-09-17, release date: 2010-11-10, Last modification date: 2024-11-06)

Primary citation

Bencsik, J.R.,Xiao, D.,Blake, J.F.,Kallan, N.C.,Mitchell, I.S.,Spencer, K.L.,Xu, R.,Gloor, S.L.,Martinson, M.,Risom, T.,Woessner, R.D.,Dizon, F.,Wu, W.I.,Vigers, G.P.,Brandhuber, B.J.,Skelton, N.J.,Prior, W.W.,Murray, L.J.
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.
Bioorg.Med.Chem.Lett., 20:7037-7041, 2010

PubMed Abstract: Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

PubMed: 20971641
DOI: 10.1016/j.bmcl.2010.09.112

Experimental method

X-RAY DIFFRACTION (2.6 Å)