Mechanism of action: Proviral integration Moloney virus (PIM) serine/threonine kinase family inhibitor
AZD1208 is an ATP competitive inhibitor of PIM-1/2/3 isoforms with IC50 values of 0.4/5/1.9nM, respectively, in enzyme assays, and inhibited substrate phosphorylation with IC50 values of 10/151/102nM, respectively, in cells.
PIM kinases are upregulated in several types of leukemias and lymphomas. Inhibition of cell proliferation is seen primarily in hematologic tumour cell lines, for example 5/14 AML cell lines tested showed growth inhibition values (GI50) of ≤1µM. Inhibition of phosphorylation of 4EBP1 and p70S6K, and suppression of mRNA translation, were the most representative effects of PIM inhibition in sensitive AML cell lines.
In vivo studies have demonstrated a clear PK/PD relationship in AML xenografts with strong suppression of pBAD, p4EBP1 and p-p70S6K for up to 12 hours post-dose. AZD1208 has also demonstrated tumour growth inhibition in other haematological and solid tumour xenograft models, and has shown enhancement of anti-tumour activity when combined with various chemotherapeutic and targeted agents.
Safety and tolerability
AZD1208 is in Phase 1 trials to evaluate the safety and tolerability profile and to determine the maximum tolerated dose (MTD). There are 2 ongoing trials where AZD1208 has been administered orally in AML and solid tumour (of all types) patients.
Preclinical toxicity studies of up to 1 month duration have been performed.
AZD1208 inhibits biomarker phosphorylation in ex vivo treated primary bone marrow aspirates from AML patients.
Target engagement has been observed in patients treated with AZD1208 as observed by biomarker inhibition consistent with inhibition of PIM kinase activity.
Suitable for and exclusions
This compound is offered for preclinical studies only at this time.
Clinical Trials for this compound
See all of the Clinical Trials currently associated with this compound:
Publications for this compound
Find out more about this compound by reading related Publications:
AZD1208, a Potent and Selective Pan-Pim Kinase Inhibitor, Demonstrates Efficacy in Preclinical Models of Acute Myeloid Leukemia
Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases
Gene information from the NCBi
This compound works on the following genes: