Details
Stereochemistry | ACHIRAL |
Molecular Formula | C32H41N9O4 |
Molecular Weight | 615.7271 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN(C)C1CCN(CC1)C(=O)c2ccc(cc2)NC(=O)Nc3ccc(cc3)-c4nc(nc(n4)N5CCOCC5)N6CCOCC6
InChI
InChIKey=DWZAEMINVBZMHQ-UHFFFAOYSA-N
InChI=1S/C32H41N9O4/c1-38(2)27-11-13-39(14-12-27)29(42)24-5-9-26(10-6-24)34-32(43)33-25-7-3-23(4-8-25)28-35-30(40-15-19-44-20-16-40)37-31(36-28)41-17-21-45-22-18-41/h3-10,27H,11-22H2,1-2H3,(H2,33,34,43)
Molecular Formula | C32H41N9O4 |
Molecular Weight | 615.7271 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/21325073Curator's Comment:: Description was created based on several sources, including http://www.pharmacodia.com/yaodu/html/v1/chemicals/0d8f8313c83e69d101e8997d3065fbff.html https://www.ncbi.nlm.nih.gov/pubmed/22261591
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21325073
Curator's Comment:: Description was created based on several sources, including http://www.pharmacodia.com/yaodu/html/v1/chemicals/0d8f8313c83e69d101e8997d3065fbff.html https://www.ncbi.nlm.nih.gov/pubmed/22261591
Gedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR, originally being developed by Wyeth. Upon intravenous administration, gedatolisib inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K. Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified clinical evaluation of Gedatolisib. Gedatolisb is in phase II clinical trials by Pfizer for the treatment of acute myeloid leukaemia. Gedatolisb is in phase I clinical trials for the treatment of solid tumours.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL4005 |
0.4 nM [IC50] | ||
Target ID: CHEMBL3267 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20166697 |
5.4 nM [IC50] | ||
Target ID: CHEMBL2842 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20166697 |
1.6 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse events |
---|---|---|
319 mg 1 times / week multiple, intravenous Highest studied dose Dose: 319 mg, 1 times / week Route: intravenous Route: multiple Dose: 319 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.6, 17 |
DLT: Mucosal inflammation, skin rash... Dose limiting toxicities: Mucosal inflammation (grade 3, 25%) Sources: Page: p.6, 17skin rash (grade 3, 25%) |
154 mg 1 times / week multiple, intravenous MTD Dose: 154 mg, 1 times / week Route: intravenous Route: multiple Dose: 154 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 42 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 42 Sources: Page: p.6, 17 |
DLT: Mucosal inflammation, AST increased... Dose limiting toxicities: Mucosal inflammation (grade 3, 2.4%) Sources: Page: p.6, 17AST increased (2.4%) ALT increased (2.4%) |
222 mg 1 times / week multiple, intravenous Studied dose Dose: 222 mg, 1 times / week Route: intravenous Route: multiple Dose: 222 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.6, 17 |
DLT: Mucosal inflammation... Other AEs: ALT increased, Mucosal inflammation... Dose limiting toxicities: Mucosal inflammation (grade 3, 42.9%) Other AEs:ALT increased (grade 2, 14.3%) Sources: Page: p.6, 17Mucosal inflammation (grade 3, 14.3%) Inflammation of mout (grade 3, 14.3%) |
266 mg 1 times / week multiple, intravenous Studied dose Dose: 266 mg, 1 times / week Route: intravenous Route: multiple Dose: 266 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: Page: p.6, 17 |
DLT: Skin rash, Hyperglycemia... Dose limiting toxicities: Skin rash (grade 3, 12.5%) Sources: Page: p.6, 17Hyperglycemia (grade 3, 12.5%) Mucosal inflammation (grade 3, 12.5%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Mucosal inflammation | grade 3, 25% DLT |
319 mg 1 times / week multiple, intravenous Highest studied dose Dose: 319 mg, 1 times / week Route: intravenous Route: multiple Dose: 319 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.6, 17 |
skin rash | grade 3, 25% DLT |
319 mg 1 times / week multiple, intravenous Highest studied dose Dose: 319 mg, 1 times / week Route: intravenous Route: multiple Dose: 319 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.6, 17 |
ALT increased | 2.4% DLT |
154 mg 1 times / week multiple, intravenous MTD Dose: 154 mg, 1 times / week Route: intravenous Route: multiple Dose: 154 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 42 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 42 Sources: Page: p.6, 17 |
AST increased | 2.4% DLT |
154 mg 1 times / week multiple, intravenous MTD Dose: 154 mg, 1 times / week Route: intravenous Route: multiple Dose: 154 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 42 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 42 Sources: Page: p.6, 17 |
Mucosal inflammation | grade 3, 2.4% DLT, Disc. AE |
154 mg 1 times / week multiple, intravenous MTD Dose: 154 mg, 1 times / week Route: intravenous Route: multiple Dose: 154 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 42 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 42 Sources: Page: p.6, 17 |
ALT increased | grade 2, 14.3% | 222 mg 1 times / week multiple, intravenous Studied dose Dose: 222 mg, 1 times / week Route: intravenous Route: multiple Dose: 222 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.6, 17 |
Inflammation of mout | grade 3, 14.3% | 222 mg 1 times / week multiple, intravenous Studied dose Dose: 222 mg, 1 times / week Route: intravenous Route: multiple Dose: 222 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.6, 17 |
Mucosal inflammation | grade 3, 14.3% | 222 mg 1 times / week multiple, intravenous Studied dose Dose: 222 mg, 1 times / week Route: intravenous Route: multiple Dose: 222 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.6, 17 |
Mucosal inflammation | grade 3, 42.9% DLT |
222 mg 1 times / week multiple, intravenous Studied dose Dose: 222 mg, 1 times / week Route: intravenous Route: multiple Dose: 222 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.6, 17 |
Hyperglycemia | grade 3, 12.5% DLT |
266 mg 1 times / week multiple, intravenous Studied dose Dose: 266 mg, 1 times / week Route: intravenous Route: multiple Dose: 266 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: Page: p.6, 17 |
Mucosal inflammation | grade 3, 12.5% DLT |
266 mg 1 times / week multiple, intravenous Studied dose Dose: 266 mg, 1 times / week Route: intravenous Route: multiple Dose: 266 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: Page: p.6, 17 |
Skin rash | grade 3, 12.5% DLT |
266 mg 1 times / week multiple, intravenous Studied dose Dose: 266 mg, 1 times / week Route: intravenous Route: multiple Dose: 266 mg, 1 times / week Sources: Page: p.6, 17 |
unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: Page: p.6, 17 |
PubMed
Title | Date | PubMed |
---|---|---|
Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. | 2010 Mar 25 |
|
PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. | 2010 Oct 1 |
|
Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. | 2011 Aug 15 |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01420081
154mg IV weekly
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21325073
In vitro, Gedatolisib potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. Gedatolisib inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Jun 26 13:51:47 UTC 2021
by
admin
on
Sat Jun 26 13:51:47 UTC 2021
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Record UNII |
96265TNH2R
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Record Status |
Validated (UNII)
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Record Version |
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-
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NCI_THESAURUS |
C2152
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NCI_THESAURUS |
C129825
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admin on Sat Jun 26 13:51:48 UTC 2021 , Edited by admin on Sat Jun 26 13:51:48 UTC 2021
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C91732
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96265TNH2R
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44516953
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1197160-78-3
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9984
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1197160-78-3
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CHEMBL592445
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DB11896
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