Abstract #3703: CAL-101, a potent and selective inhibitor of the class 1 phosphatidylinositol 3 kinase (PI3K) p110\#948;: Preclinical summary

Abstract

Background: One of the most frequently observed defects in human malignancies is the deregulation of the PI3K/Akt pathway, and several genetic and inhibitor studies indicate that the PI3K isoforms play an important role in tumor growth. The phosphorylated lipid product, PIP3, controls numerous processes including cell growth, survival, differentiation, and chemotaxis. For the Class 1 isoforms, \#945;, \#946;, \#948; and \#947;, drug discovery programs focused on the p110\#945; isoform have observed side effects including elevations in plasma glucose and insulin due to the broad distribution of the p110\#945; isoform and its key role in insulin signaling. Further, in contrast to the embryonic lethal p110\#945; and p110\#946; knockouts, mice with a deletion of p110\#948; are viable and fertile with specific decreases in B-cell survival and function. The pharmacological properties of an orally administered inhibitor of the p110\#948; isoform of PI3K, CAL-101, demonstrate a favorable therapeutic index in a variety of non-clinical pharmacology and safety studies. Methods: CAL-101 was assessed for pharmacological qualities in a variety of in vitro assays and in vivo studies, including acute and subchronic GLP safety studies in rats and dogs. Results: In enzymatic and cell-based assays, CAL-101 was observed to have low nM potency against p110\#948; kinase with greater than 30-500 fold selectivity against other lipid kinases and >10,000-fold selectivity against the wider kinome. Induction of apoptosis in cells from patients with hematologic malignancies has been observed with CAL-101. No significant human ion channel, receptor or cytochrome p450 drug metabolizing enzyme inhibition was observed at any concentration tested. In rats and dogs, CAL-101 was found to have 39 and 79% oral bioavailability, respectively. In 28 day non-clinical safety studies in rats and dogs, a wide therapeutic index was observed even at plasma drug levels well above those needed for complete target inhibition. In the rats, there was a dose-related decrease in secondary follicles of the lymph nodes and Peyer\#8217;s patches, a decrease in marginal zone lymphocytes of the spleen, and cortical lymphocyte depletion in the thymus as well as reversible decreases in total peripheral leukocytes. Immunohistochemistry showed a reversible dose-related decrease in B-cell and T-cell populations in lymphoid organs that corresponded with the microscopic findings in these tissues. These observations are consistent with the phenotype observed in p110\#948; knockout mice. Conclusion: CAL-101 is a potent, selective and highly active inhibitor of p110\#948; in a variety of non-clinical models. Effects can be demonstrated on target cells and tissues in vivo that are consistent with the intended target and mode of action, and a wide therapeutic index has been established to enable clinical studies in normal volunteers, cancer and inflammatory diseases.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3703.