Abstract #2013: Discovery of SGI-1776, a potent and selective Pim-1 kinase inhibitor Free

Pim-1 is a highly conserved serine-threonine kinase that is a key regulator in many cytokine signaling pathways. Activated Pim-1 kinase can induce progression of the cell cycle, inhibition of apoptosis, and modulation of other signal transduction pathways, including its own. Transformation of Pim-1 kinase in conjunction with other oncogenes such as c-myc, N-Myc, and others such as gfi-1, runx-2 leads to malignancies including Burkitt\#8217;s lymphoma, prostate cancer, diffuse large cell lymphoma several other types of human leukemias. These findings suggest that Pim-1 may be a promising drug target for development of anticancer agents. Through the use of Pim-1kinase crystal structure we began our discovery process by performing large-scale virtual screening composed of focused and or diverse virtual libraries. With the application of consensus scoring, binding energies and several drug-like filters we have selected limited set of 72 compounds. Five compounds belongs to imidazo[1,2-b]pyridzaine series were found to inhibit the Pim-1 kinase enzyme with an IC₅₀ from 2 to 10 \#956;M. These active compounds and their binding modes lead to the lead optimization, synthesis and for further design of potent Pim1 kinase inhibitors. The strategies for optimizing the potency and selectivity against the Pim-1 target were undertaken with the focus on the modifications of R₁ and R₂ groups. A novel synthetic route was developed starting from 1,4-dibromo-trans-2-butene. We prepared 3-bromo-6-chloro-imidazo[1,2-b]pyridazine scaffold in three steps. Suzuki coupling with various substituted aryl boronic acids and followed by introduction of aliphatic amines lead to the synthesis of more than 30 novel chemical entities as Pim-1 kinase inhibitors. Initial SAR studies revealed that the introduction of hydrophobic moiety at R₁ and small ring substituent groups with 1 or 2 -CH₂ spacer at the 6-amine position are vital for the Pim-1 kinase inhibition. The lead compound SGI-1776 showed very potent activity against Pim-1 kinase with an IC₅₀ of 7 nM and kinases selectivity. We recently filed an IND and anticipate enrollment into the First-in-Human Phase I study in the near future. Design, synthesis and SAR studies will be presented.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2013.