Abstract 3834: 3-ethynyl-1H-indazoles as inhibitors of PI3k signaling pathway

A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1 and mTOR kinases. Combination of computational modeling and structure-activity relationships studies reveal a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays anti-proliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could result useful in deriving novel selecting and multi-kinase inhibitors for clinical use. 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 3834. doi:10.1158/1538-7445.AM2011-3834