Abstract 3603: Development of novel small molecule PIM kinase inhibitors

Abstract

Abstract The PIM family of serine/threonine kinases, regulated by cytokines and growth factors, is over-expressed in multiple cancer types, including prostate tumors and hematologic malignancies. Recent reports of PIM kinase inhibitors have been implicated with anti-tumor growth activity in cancer cells and xenograft models, thus providing evidence that PIM kinases are attractive targets for anticancer drug development. Jasco Pharmaceuticals has developed a proprietary focused screening library of small molecules designed to inhibit PIM kinase activity. Kinase panel screening of the focused set identified nanomolar inhibitors from a novel chemical series. To further characterize the compounds, Jasco Pharma has established a research partnership with Crown BioScience for access to its cancer cell line and human primary tumor (HuPrime) xenograft models. The initial efforts of this partnership involved the identification of cancer cell lines which express high levels of PIM kinases for anti-proliferation studies and MOA exploration. Medicinal chemistry optimization provided a cluster of compounds with low single-digit micromolar anti-proliferation activity. These improved compounds have been demonstrated to act through a PIM driven mechanism of action, decreasing the levels of the proto-oncogene c-myc and the phosphorylation of the proteins BAD and 4E-BP1. In order to select the compounds with better in vivo drug activity, we performed in vivo PK followed by plasma protein binding assay (PPB) and drug-drug interaction (DDI) analysis instead of the whole series of in vitro ADME property assays. Four compounds were picked up for in vivo efficacy study according to their potency, in vivo pk characteristics, results of PPB and DDI. Preliminary results indicated that one compound had significant anti-tumor activity in MV-4-11 tumor models. 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 3603. doi:10.1158/1538-7445.AM2011-3603