3MJW

PI3 Kinase gamma with a benzofuranone inhibitor

Summary for 3MJW

• Entry DOI: 10.2210/pdb3mjw/pdb
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, (2Z)-4,6-dihydroxy-2-[(8-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indol-10-yl)methylidene]-1-benzofuran-3(2H)-one (2 entities in total)
• Functional Keywords: atp-binding, kinase, nucleotide-binding, transferase
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 111134.54

Authors

Bard, J.,Svenson, K. (deposition date: 2010-04-13, release date: 2010-06-09, Last modification date: 2023-09-06)

Primary citation

Zhang, N.,Ayral-Kaloustian, S.,Anderson, J.T.,Nguyen, T.,Das, S.,Venkatesan, A.M.,Brooijmans, N.,Lucas, J.,Yu, K.,Hollander, I.,Mallon, R.
5-Ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.
Bioorg.Med.Chem.Lett., 20:3526-3529, 2010

PubMed Abstract: A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.

PubMed: 20483602
DOI: 10.1016/j.bmcl.2010.04.139

Experimental method

X-RAY DIFFRACTION (2.87 Å)