Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C21H21N3O2S |
| Molecular Weight | 379.475 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
N[C@@H]1CCCN(C1)C2=C(C=CC=C2\C=C3/SC(=O)NC3=O)C4=CC=CC=C4
InChI
InChIKey=MCUJKPPARUPFJM-UWCCDQBKSA-N
InChI=1S/C21H21N3O2S/c22-16-9-5-11-24(13-16)19-15(12-18-20(25)23-21(26)27-18)8-4-10-17(19)14-6-2-1-3-7-14/h1-4,6-8,10,12,16H,5,9,11,13,22H2,(H,23,25,26)/b18-12-/t16-/m1/s1
| Molecular Formula | C21H21N3O2S |
| Molecular Weight | 379.475 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 1 |
| Optical Activity | UNSPECIFIED |
AZD-1208 is an orally available, potent and highly selective Pim inhibitor that effectively inhibits all three isoforms. AZD-1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of Pim-1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD-1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in phosphorylation of BAD, 4EBP1 and p70S6K. In addition, AZD-1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of Pim targets. AZD-1208 was in Phase 1 trials to evaluate the safety and tolerability profile and to determine the maximum tolerated dose (MTD). There were two trials where AZD-1208 had been administered orally in AML and solid tumour (of all types) patients. The studies had being discontinued due to safety reasons.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL2147 |
0.1 nM [Ki] | ||
Target ID: CHEMBL4523 |
1.92 nM [Ki] | ||
Target ID: CHEMBL5407 |
0.4 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
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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 |
|---|---|---|---|---|
3844 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29765150 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AZD-1208 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
75000 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29765150 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AZD-1208 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
37.2 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29765150 |
800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: |
AZD-1208 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Sample Use Guides
In Vivo Use Guide
Curator's Comment: Humans - Acute Myelogenous Leukemia treatment: Daily oral doses of AZD-1208 for 28 day cycles until progression or unacceptable toxicity develops. Starting dose will be 120 mg and will be escalated in successive cohorts until an MTD is established. https://clinicaltrials.gov/ct2/show/NCT01489722
Mice: The in vivo activity of AZD-1208 was assessed in a MOLM-16 xenograft model treated daily for 2 weeks with drug or vehicle control. Dose-dependent inhibition of MOLM-16 tumor growth was observed. Treatment with 10 mg/kg or 30 mg/kg of AZD-1208 (the latter representing the typical maximum-tolerated dose on this treatment schedule) led to 89% tumor growth inhibition or slight regression, respectively. PD analyses following a single dose of 30 mg/kg showed strong suppression of pBAD, p4EBP1, and p-p70S6K for up to 12 hours after dosing.
Route of Administration:
Oral
In enzymatic assays carried out at a concentration of ATP that leads to half-maximal reaction velocity, AZD-1208 inhibited kinase activity with an IC50 of 0.4 nM for Pim-1, 5.0 nM for Pim-2, and 1.9 nM for Pim-3. In enzyme assays using 5 mM ATP, the high end of physiologic ATP concentration in human cells, the IC50 values were 2.6 nM for Pim-1, 164 nM for Pim-2, and 17 nM for Pim-3.
| Substance Class |
Chemical
Created
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admin
on
Edited
Mon Mar 31 21:01:09 GMT 2025
by
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on
Mon Mar 31 21:01:09 GMT 2025
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| Record UNII |
S98NFM1378
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| Record Status |
Validated (UNII)
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| Record Version |
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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TARGET -> INHIBITOR |
COMPETITIVE INHIBITOR
IC50
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TARGET -> INHIBITOR |
COMPETITIVE INHIBITOR
IC50
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SALT/SOLVATE -> PARENT | |||
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TARGET -> INHIBITOR |
COMPETITIVE INHIBITOR
IC50
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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ACTIVE MOIETY |
