4G11

X-ray structure of PI3K-gamma bound to a 4-(morpholin-4-yl)- (6-oxo-1,6-dihydropyrimidin-2-yl)amide inhibitor

Summary for 4G11

• Entry DOI: 10.2210/pdb4g11/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide (2 entities in total)
• Functional Keywords: phosphoinositide 3-kinase gamma, secondary messenger generation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111041.44

Authors

Morales, R. (deposition date: 2012-07-10, release date: 2012-11-14, Last modification date: 2023-09-13)

Primary citation

Certal, V.,Halley, F.,Virone-Oddos, A.,Thompson, F.,Filoche-Romme, B.,El-Ahmad, Y.,Carry, J.C.,Delorme, C.,Karlsson, A.,Abecassis, P.Y.,Vincent, L.,Bonnevaux, H.,Nicolas, J.P.,Morales, R.,Michot, N.,Vade, I.,Louboutin, A.,Perron, S.,Doerflinger, G.,Tric, B.,Monget, S.,Lengauer, C.,Schio, L.
Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3K beta inhibitors
Bioorg.Med.Chem.Lett., 22:6381-6384, 2012

PubMed Abstract: From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.

PubMed: 22981333
DOI: 10.1016/j.bmcl.2012.08.072

Experimental method

X-RAY DIFFRACTION (3.4 Å)