3ZIM

Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kalpha

Summary for 3ZIM

• Entry DOI: 10.2210/pdb3zim/pdb
• Descriptor: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM, 1-[4-[[2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-6-methyl-hept-5-ene-1,4- dione (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 109980.19

Authors

Nacht, M.,Qiao, L.,Sheets, M.P.,Martin, T.S.,Labenski, M.,Mazdiyasni, H.,Karp, R.,Zhu, Z.,Chaturvedi, P.,Bhavsar, D.,Niu, D.,Westlin, W.,Petter, R.C.,Medikonda, A.P.,Jestel, A.,Blaesse, M.,Singh, J. (deposition date: 2013-01-09, release date: 2013-02-13, Last modification date: 2024-10-23)

Primary citation

Nacht, M.,Qiao, L.,Sheets, M.P.,Martin, T.S.,Labenski, M.,Mazdiyasni, H.,Karp, R.,Zhu, Z.,Chaturvedi, P.,Bhavsar, D.,Niu, D.,Westlin, W.,Petter, R.C.,Medikonda, A.P.,Singh, J.
Discovery of a Potent and Isoform-Selective Targeted Covalent Inhibitor of the Lipid Kinase Pi3Kalpha
J.Med.Chem., 56:712-, 2013

PubMed Abstract: PI3Kα has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the α isoform, and that PI3Kβ, -γ, and -δ are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kα.

PubMed: 23360348
DOI: 10.1021/JM3008745

Experimental method

X-RAY DIFFRACTION (2.85 Å)