Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains.
The PI3-kinase (PI3K) pathway regulates many cellular processes, especially cell metabolism, cell survival, and apoptosis. Phosphatidylinositol-3,4,5-trisphosphate (PIP3), the product of PI3K activity and a key signaling molecule, acts by recruiting pleckstrin-homology (PH) domain-containing proteins to cell membranes. Here, we describe a new structural class of nonphosphoinositide small molecule antagonists (PITenins, PITs) of PIP3-PH domain interactions (IC(50) ranges from 13.4 to 31 μM in PIP3/Akt PH domain binding assay). PITs inhibit interactions of a number of PIP3-binding PH domains, including those of Akt and PDK1, without affecting several PIP2-selective PH domains. As a result, PITs suppress the PI3K-PDK1-Akt pathway and trigger metabolic stress and apoptosis. A PIT-1 analog displayed significant antitumor activity in vivo, including inhibition of tumor growth and induction of apoptosis. Overall, our studies demonstrate the feasibility of developing specific small molecule antagonists of PIP3 signaling.
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Benchun
B
Miao
Igor
I
Skidan
Jinsheng
J
Yang
Alexey
A
Lugovskoy
Mikhail
M
Reibarkh
Kai
K
Long
Tres
T
Brazell
Kulbhushan A
KA
Durugkar
Jenny
J
Maki
C V
CV
Ramana
Brian
B
Schaffhausen
Gerhard
G
Wagner
Vladimir
V
Torchilin
Junying
J
Yuan
Alexei
A
Degterev
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects
D001798:Blood Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D054852:Small Molecule Libraries; C060974:phosphatidylinositol 3,4,5-triphosphate; C039077:platelet protein P47; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase