Uses
AZD1208 is a potent, and orally available Pim kinase inhibitor.
Biological Activity
upregulation of pim kinases has been observed in several types of leukemias and lymphomas. pim-1, -2, and -3 promote cell proliferation and survival downstream of cytokine and growth factor signaling pathways. azd1208 is a potent, highly selective, and orally available pim kinase inhibitor.
in vitro
azd1208 inhibited the growth of 5 of 14 acute myeloid leukemia (aml) cell lines tested. in molm-16 cells, azd1208 also causes cell cycle arrest and apoptosis, accompanied by a dose-dependent reduction in phosphorylation of bcl-2 antagonist of cell death [1].
Enzyme inhibitor
This orally available protein kinase inhibitor (FW = 379.48 g/mol; CAS
1204144-28-4; Soluble in DMSO, Insoluble in H2O), also named 5-[[2-
[ (3R) -3-aminopiperidin-1-yl]biphenyl-3-yl]methylidene]-1,3-thiazolidine-
2,4-dione, targets the proto-oncogene serine/threonine-protein kinases
PIM-1, PIM-2 and PIM-3, often interrupting the G1/S cell cycle transition
and inducing apoptosis in PIM-overexpressing cells. Pim kinases are
downstream effectors of ABL, JAK2, and Flt-3 oncogenes that are critical
for driving tumorigenesis. PIM1, PIM2 and PIM3 were first recognized
as pro-viral integration sites for the Moloney Murine Leukemia virus.
Unlike other kinases, they possess a hinge region which creates a unique
binding pocket for ATP. Absence of a regulatory domain makes these
proteins are constitutively active once transcribed. Upregulation of Pim
kinases is observed in several types of leukemias (especially Acute
Myelogenous Leukemia (AML) ) and lymphomas, with PIM-1, PIM-2 and
PIM-3 promoting cancer cell proliferation and survival. AZD1208,
demonstrates efficacy in preclinical models of acute myeloid leukemia.
in vivo
azd1208 inhibits the growth of kg-1a and molm-16 xenograft tumors in vivo with a clear pk/pd relationship. treatment with 10 mg/kg or 30 mg/kg of azd1208 led to an 89% tumor growth inhibition or slight regression, respectively [1].
IC 50
0.4 nm for pim-1, 5.0 nm for pim-2, and 1.9 nm for pim-3
References
[1] keeton ek, mceachern k, dillman ks, palakurthi s, cao y, grondine mr, kaur s, wang s, chen y, wu a, shen m, gibbons fd, lamb ml, zheng x, stone rm, deangelo dj, platanias lc, dakin la, chen h, lyne pd, huszar d. azd1208, a potent and selective pan-pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. blood. 2014;123(6):905-13.
