Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C18H17Cl2FN4OS |
Molecular Weight | 427.323 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1N=CC(Cl)=C1C2=C(Cl)SC(=C2)C(=O)N[C@H](CN)CC3=CC=CC(F)=C3
InChI
InChIKey=AFJRDFWMXUECEW-LBPRGKRZSA-N
InChI=1S/C18H17Cl2FN4OS/c1-25-16(14(19)9-23-25)13-7-15(27-17(13)20)18(26)24-12(8-22)6-10-3-2-4-11(21)5-10/h2-5,7,9,12H,6,8,22H2,1H3,(H,24,26)/t12-/m0/s1
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/24978597Curator's Comment: Description was created based on several sources, including
http://www.bloodjournal.org/content/118/21/1856 http://adisinsight.springer.com/drugs/800033693
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597
Curator's Comment: Description was created based on several sources, including
http://www.bloodjournal.org/content/118/21/1856 http://adisinsight.springer.com/drugs/800033693
Afuresertib (GSK2110183 ) is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Preclinically, AKT inhibition by afuresertib can reverse platinum resistance in ovarian cancer cell lines isolated from patients with platinum-resistant ovarian cancer. Afuresertib is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Is in phase II clinical trials for Chronic lymphocytic leukaemia; Haematological malignancies; Histiocytosis.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597 |
0.08 nM [Ki] | ||
Target ID: CHEMBL2431 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597 |
2.0 nM [Ki] | ||
Target ID: CHEMBL4816 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597 |
2.6 nM [Ki] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
949 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
554 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
531 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
13425 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
6782 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
7405 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/ |
125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
AFURESERTIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/25075128
Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597
Afuresertib inhibits the kinase activity of the E17K AKT1 mutant protein with EC50 of 0.2 nM. Afuresertib shows a concentration-dependent effect on multiple AKT substrate phosphorylation levels, including GSK3b, PRAS40, FOXO and Caspase 9. Overall 65% of the hematological cell lines are sensitive to afuresertib (EC50 < 1 uM).
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NCI_THESAURUS |
C155764
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ZZ-02
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100000168977
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46843057
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C82390
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DTXSID60146711
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DB11648
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SUB182525
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1047644-62-1
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8739X25QI3
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CHEMBL2219422
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)