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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
Structure of AZD-1208

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

HIDE SMILES / InChI

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.

CNS Activity

Curator's Comment: AZD-1208 demonstrates CNS penetration in preclinical radioactivity distribution studies.

Approval Year

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors.
2013 Dec 12
Patents

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
by admin
on Sat Dec 16 01:49:00 GMT 2023
Edited
by admin
on Sat Dec 16 01:49:00 GMT 2023
Record UNII
S98NFM1378
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AZD-1208
Common Name English
AZD 1208 [WHO-DD]
Common Name English
Code System Code Type Description
SMS_ID
100000175798
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
PUBCHEM
58423153
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
ChEMBL
CHEMBL3545423
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
CAS
1204144-28-4
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
EPA CompTox
DTXSID801026025
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
FDA UNII
S98NFM1378
Created by admin on Sat Dec 16 01:49:00 GMT 2023 , Edited by admin on Sat Dec 16 01:49:00 GMT 2023
PRIMARY
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