Abstract 4489: Preclinical profile of novel, potent, and selective PI3K delta inhibitors
Authors: Vakkalanka Swaroop , Muthuppalaniappan Meyyappan , G Babu , Varanasi Kanthikiran VS , Veeraraghavan Sridhar , Viswanadha Srikant 
Published: June 2012

Background: Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3 position hydroxyl group of the inositol ring of phosphotidylinositol. The PI3K pathway is frequently activated in human cancers and thus represents an attractive target for small molecule inhibitors. Pan-PI3K inhibitors currently in development have been associated with adverse side-effects such as insulin resistance, thus necessitating the need to develop isoform specific inhibitors of PI3K. Herein, we describe the biological and pharmacokinetic properties of representative molecules from a series of novel and small molecule PI3KΔ inhibitors with scope to be further developed as clinical candidates for hematological malignancies such as acute myeloid leukemia and Non-Hodkin's lymphoma.

Methods: Activity of test compounds on individual PI3K isoforms was determined by a Homogenous Time Resolved Fluorescence assay (Millipore, Billerica, MA) with modifications. Cell based selectivity assays against α, β, or γ isoforms was assessed by testing the effect of the compounds on PDGF, LPA, or c5a induced Akt phosphorylation in NIH-3T3 or RAW cells. Similarly, inhibition of cellular PI3KΔ activity was determined in a IgM induced human B-cell proliferation assay. Cell viability assay was conducted to determine the growth inhibitory effect of the compounds in cell lines representative of human acute and chronic leukaemia and lymphoma. Pharmacokinetic behaviour of compounds in plasma after single dose oral administration was determined in female Balb/c mice.

Results: Among the compounds evaluated, RP5175 and RP5182 inhibited PI3KΔ activity in enzyme and cell based assays with IC50 values of 9.6 & 37.3 nM and EC50 values of 7.6 & 18.9 nM respectively. Besides, the compounds displayed a high degree of selectivity over the alpha (&gt;500 fold), beta (&gt;400 fold), and gamma (&gt;15-40 fold) isoforms. Viability assays demonstrated that the compounds caused a significant inhibition in growth of THP-1, TOLEDO, and HL-60 cells. Pharmacokinetic studies in female Balb/c mice indicated good oral absorption with favourable peak plasma concentrations.

Conclusions: Results demonstrate the PI3K delta selective nature of RP5175 and 5182 along with an ability to suppress proliferation of cancer cells. In vitro selectivity and potency data indicate the therapeutics potential of the compounds in hematological cancers without the deleterious effects commonly associated with the Pan PI3K inhibitors. The compounds are currently being tested for in vitro and in vivo efficacy across various cancer cell lines and xenograft models besides selectivity against other kinases.

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 4489. doi:10.1158/1538-7445.AM2011-4489