Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα.
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.
Celgene Avilomics Research, 45 Wiggins Avenue, Bedford, Massachusetts 01730, USA. mnacht@celgene.com
Mariana
M
Nacht
Lixin
L
Qiao
Michael P
MP
Sheets
Thia
T
St Martin
Matthew
M
Labenski
Hormoz
H
Mazdiyasni
Russell
R
Karp
Zhendong
Z
Zhu
Prasoon
P
Chaturvedi
Deepa
D
Bhavsar
Deqiang
D
Niu
William
W
Westlin
Russell C
RC
Petter
Aravind Prasad
AP
Medikonda
Juswinder
J
Singh
D000818:Animals; D055808:Drug Discovery; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D019906:Nuclear Magnetic Resonance, Biomolecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors