Abstract 2790: Discovery of novel Pim-1 inhibitors

Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. Recently, Pim-1 has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors. As part of our continuing efforts to identify potential protein targets and inhibitors in the area of cancer treatment, we selected Pim-1 target and used fragment drug discovery platform to undertake the efforts in identification of novel inhibitors. Over 1800 fragments have been screened using SPR binding assay, followed by PIM1 kinase inhibition assay. Among many active fragments, we identified an interesting small fragment, 5-bromobenzofuran-2-carboxylic acid (1), which has IC50 of 8.1 uM in the Pim-1 kinase inhibition assay. The X-ray structure of 1 binding to Pim-1 revealed that the oxygen of the benzofuran is positioned towards the hinge site while the carboxylic acid interacts directly with the Lys-67. Guided by the X-ray structures, we generated many more potent inhibitors, among which, compound 2 with an aminicyclohexayl moiety at the 7-position is one of the most potent inhibitor with IC50 of 0.001uM in Pim-1 kinase inhibition assay. X-ray structure of 2 binding to Pim-1 indicated that compound 2 gained additional interactions by directly interacting of its nitrogen atom of the aminocycloheaxyl group with Asp127 as well as interacting through water bridges with Glu170 and Asn 171. Compound 2 has also potent activity in inhibiting Pim-2 with IC50 of 0.004 uM while is highly selective against most kinases in the Ambit kinase panel. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2011-2790