Pim (Provirus Integration site for Moloney murine leukemia virus) proteins are highly conserved serine/threonine kinases (PIM1, PIM2 and PIM3) that are constitutively activated in a variety of hematopoietic and solid malignancies. [1
] They are thought to exert an oncogenic effect primarily via regulation of Myc family protein transcriptional activity. Evidence for this comes from PIM1 transgenic mice that have been shown to develop clonal T cell lymphomas when infected with murine leukemia virus via increased myc activation due to proviral insertion near myc genes [4
], indicating cooperation between MYC and PIM1 in lymphomagenesis [6
]. Pim kinases also appear to function to suppresses apoptosis [7
], modulate migration [8
], inducing genomic instability via disruptions in mitotic spindle checkpoints [9
], influencing angiogenesis [10
] and modulating cell cycle regulation [11
Pim kinases are over-expressed in a variety of human cancers including CLL, mantle cell lymphoma, diffuse large B cell lymphoma, FLT3/ITD AML and solid tumors including prostate, pancreas and colon [14
], and aberrant expression may be associated with outcome. In view of the role in cell differentiation, angiogenesis, survival and proliferation PIM kinase inhibition provides a tractable therapeutic target for several pediatric malignancies.
Unlike other kinases, PIM proteins do not posses the typical canonical hydrogen bond donor in the hinge region (due to the presence of a proline residue instead of methionine)[15
], a typical key binding sight for many small molecules. SGI-1776 is an imidazo [1,2-b]pyridazine compound that was discovered as a potential novel inhibitor of the PIM kinases with IC50
concentrations for PIM1, PIM2 and PIM3 of 7 nM, 363 nM and 69 nM, respectively. It is relatively specific with some on target activity against FLT3 and the haspin group of kinases. SGI-1776 has shown preclinical activity against leukemia and solid tumor cell line models [16
] with IC50
values of 0.005-11.68 μM. Preclinical in vivo
studies with human-derived myeloid leukemia xenograft models showed that SGI- 1776 was extremely active as an orally delivered drug and induced complete tumor regression. The PPTP therefore performed preclinical testing to assess the potential activity of SGI-1776 against pediatric cancers.