PF-04691502

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Synonyms
Status
Molecule Category UNKNOWN
UNII 4W39NS61KI

Structure

InChI Key XDLYKKIQACFMJG-WKILWMFISA-N
Smiles COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@H](OCCO)CC3)c2=O)cn1
InChI
InChI=1S/C22H27N5O4/c1-13-17-11-18(14-3-8-19(30-2)24-12-14)21(29)27(20(17)26-22(23)25-13)15-4-6-16(7-5-15)31-10-9-28/h3,8,11-12,15-16,28H,4-7,9-10H2,1-2H3,(H2,23,25,26)/t15-,16-

Physicochemical Descriptors

Property Name Value
Molecular Formula C22H27N5O4
Molecular Weight 425.49
AlogP 2.25
Hydrogen Bond Acceptor 9.0
Hydrogen Bond Donor 2.0
Number of Rotational Bond 6.0
Polar Surface Area 125.38
Molecular species NEUTRAL
Aromatic Rings 3.0
Heavy Atoms 31.0

Bioactivity

Mechanism of Action Action Reference
PI3-kinase class I inhibitor INHIBITOR PubMed PubMed
Protein: PI3-kinase class I
Description: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Organism : Homo sapiens
O00329 ENSG00000171608
Protein: PI3-kinase class I
Description: Phosphatidylinositol 3-kinase regulatory subunit beta
Organism : Homo sapiens
O00459 ENSG00000105647
Protein: PI3-kinase class I
Description: Phosphatidylinositol 3-kinase regulatory subunit alpha
Organism : Homo sapiens
P27986 ENSG00000145675
Protein: PI3-kinase class I
Description: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Organism : Homo sapiens
P42336 ENSG00000121879
Protein: PI3-kinase class I
Description: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform
Organism : Homo sapiens
P42338 ENSG00000051382
Protein: Serine/threonine-protein kinase mTOR
Description: Serine/threonine-protein kinase mTOR
Organism : Homo sapiens
P42345 ENSG00000198793
Protein: PI3-kinase class I
Description: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Organism : Homo sapiens
P48736 ENSG00000105851
Protein: PI3-kinase class I
Description: Phosphoinositide 3-kinase regulatory subunit 5
Organism : Homo sapiens
Q8WYR1 ENSG00000141506
Protein: PI3-kinase class I
Description: Phosphatidylinositol 3-kinase regulatory subunit gamma
Organism : Homo sapiens
Q92569 ENSG00000117461
Targets EC50(nM) IC50(nM) Kd(nM) Ki(nM) Inhibition(%)
Enzyme Kinase Protein Kinase AGC protein kinase group AGC protein kinase AKT family
- 13 - - -
Enzyme Kinase Protein Kinase Atypical protein kinase group Atypical protein kinase PIKK family Atypical protein kinase FRAP subfamily
- 8-8 - 16-16 -
Enzyme Transferase
- 3-8 - 1-1 -
Assay Description Organism Bioactivity Reference
Inhibition of PI3Kalpha None 0.57 nM
Inhibition of mTOR None 16.0 nM
Inhibition of AKT phosphorylation at Ser 473 in human BT20 cells Homo sapiens 13.0 nM
Inhibition of mTOR (unknown origin) Homo sapiens 16.0 nM
Inhibition of mouse PI3Kalpha Mus musculus 0.57 nM
Inhibition of mTOR (unknown origin) after 40 mins by TR-FRET assay Homo sapiens 7.9 nM
Inhibition of PI3Kalpha (unknown origin) using PIP2/PS as substrate compound preincubated for 15 mins by luciferase-based luminescence assay Homo sapiens 8.33 nM
Inhibition of mouse PI3K alpha expressed in insect cells coexpressing p85 subunit assessed as PI(3,4,5)P3 formation using PI(4,5)P2 as substrate by measuring displacement of TAMRA-labeled PI(3,4,5)P3 from Grip1 PH domain after 35 mins by ligand displacement fluorescence polarization assay Mus musculus 0.57 nM
Inhibition of recombinant mTOR (unknown origin) assessed as GFP-4E-BP1 substrate phosphorylation after 20 mins by TR-FRET assay Homo sapiens 16.0 nM
Inhibition of AKT phosphorylation at S473 in human BT20 cells after 1 hr by sandwich ELISA Homo sapiens 13.0 nM
Inhibition of AKT phosphorylation at S473 in human SKOV3 cells after 1 hr by sandwich ELISA Homo sapiens 7.4 nM
Inhibition of PI3Kalpha (unknown origin) using PIP2/PS as substrate preincubated for 15 mins before substrate addition by luciferase-based luminescence assay Homo sapiens 8.33 nM
Inhibition of mTOR (unknown origin) assessed as inhibition of 4EBP-1 phosphorylation preincubated for 15 mins before substrate addition by TR-FRET assay Homo sapiens 7.9 nM
Antiproliferative activity against human SKOV3 cells after 3 days by CellTiter-Glo assay Homo sapiens 290.0 nM
Antiproliferative activity against human U87MG cells after 4 days by CellTiter-Glo assay Homo sapiens 520.0 nM
Biochemical Assay: Compounds of the present invention were evaluated for potency against PI3-Kα using an in vitro kinase assay. PI3-Kα activity is measured in vitro by determining the level of phosphorylation of the substrate PI(4,5)P2. The formation of product PI(3,4,5)P3 is monitored by binding to the Grip1 PH domain in a ligand displacement fluorescence polarization (FP) assay, in which the TAMRA-labeled PI(3,4,5)P3 complexed with Grip1 PH domain is displaced by PI(3,4,5)P3 formed in the PI3-Kα reaction resulting in a decrease in FP signal. Homo sapiens 4.85 nM
Inhibition of PI3Kalpha (unknown origin) using PIP2 as substrate by Kinase-Glo assay Homo sapiens 3.3 nM
Cytotoxicity against human NCI-H460 cells after 96 hrs by MTT assay Homo sapiens 200.0 nM
Antiproliferative activity against human U87MG cells after 4 days by Celltiter-Glo luminescence cell viability assay Homo sapiens 340.0 nM
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging Homo sapiens -12.79 %
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate Severe acute respiratory syndrome coronavirus 2 107.19 % SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate Severe acute respiratory syndrome coronavirus 2 100.52 %
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 17.8 % Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 13.48 % Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 13.48 % Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 17.8 %
Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 550.0 nM Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 800.0 nM Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 550.0 nM Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus 800.0 nM

Cross References

Resources Reference
ChEMBL CHEMBL1234354
DrugBank DB11974
FDA SRS 4W39NS61KI
Guide to Pharmacology 7936
PDB ML9
PubChem 25033539
SureChEMBL SCHEMBL1381425
ZINC ZINC000117704832
CONTENTS