AZD1208 is an Orally Bioavailable and Highly Selective PIM Kinases Inhibitor
Posted On 2021-04-28
Pim kinases, also known as serine/threonine kinases, have three highly homologous isoforms namely Pim-1, Pim-2, and Pim-3. And Pim-1, Pim-2, and Pim-3 are recurrent proviral integration locus in Moloney murine leukemia virus. The overexpression of Pim kinases occurs when viral inserts at this site. Pim kinases are overexpressed in several tumour types, contributing to oncogenesis. For example, PIM1 is overexpressed in haematopoietic malignancies, especially in acute myeloid leukaemia and acute lymphoblastic leukaemia.
AZD1208 is a potent, selective, ATP-competitive, and orally active pan-Pim kinase inhibitor. AZD1208 shows high affinity for Pim-1, Pim-2, and Pim-3 with Ki values of 0.1 nM, 1.92 nM, and 0.4 nM, respectively. In acute myeloid leukemia (AML) cell lines, EOL-1, KG-1a, Kasumi-3, MV4-11, and MOLM-16 cells, AZD1208 inhibits these AML cells growth with GI50 values of <1 μM. AZD1208 induces cell-cycle arrest and apoptosis. Because in MOLM-16 cells, AZD1208 increases the G0/G1 and subG1 population in a dose-dependent manner. And AZD1208 also inhibits Bcl-2 antagonist of cell death (BAD) phosphorylation on Ser 112. Moreover, AZD1208 also reduces the phosphorylation of 4EBP1, p70S6K, and S6. In addition, AZD1208 increases the cleaved caspase 3 and p27 in MOLM-16 cells.
Additionally, in Flt3 wild-type or Flt3 internal tandem duplication leukemic cells, AZD1208 displays effective inhibition in colony growth and Pim signaling substrates.
In summary, AZD1208 is a selective and orally active pan-Pim kinase inhibitor. AZD1208 inhibits the tumor growth of MOLM-16 and KG-1a xenografts with a clear pharmacodynamic-pharmacokinetic relationship. AZD1208 inhibits the viability of acute myeloid leukemia and solid tumor cells.
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