Signal transduction therapy of colon tumors with multiple target kinase inhibitors

Signal transduction therapy is a leading area of modern drug research aiming to inhibit the pathomechanism based validated target molecules in cellular signaling. Selective inhibition of these false proliferative signals via targeting receptor tyrosine kinases and other signaling enzymes, resulting in the induction of apoptosis by depletion of the survival factors is one of the most studied concept of modern chemotherapy. Our Nested Chemical Library™ (NCL) technology is based on a knowledge base approach where focused libraries of kinase inhibitors (KIs) around 108 core structures and hundreds of scaffolds are used for hit finding and to generate pharmacophore models. We established a unique proprietary kinase inhibitory chemistry and developed nM lead molecules against a series of kinases. In order to overcome treatment resistance (to the apoptosis-inducing effects of chemotherapeutic agents) and develop new drugs that target genes and protein products in the apoptosis pathways we developed multiple target KIs to inhibit certain survival factors and induce synthetic lethality in cancer cells. We investigated synthetic lethal interactions for the identification of new and more powerful classes of drug targets. The pro-apoptotic effect of the compounds of Vichem's Chemical Validation Library (CVL) was tested on two isogenic cell lines by sub-G1 flow cytometric apoptosis assay and lead molecules were selected. Our novel “Target Fishing“ technology is aimed for selectivity profiling of lead molecules. We employed proteomic methods to characterize the cellular targets of KIs. Besides selectivity profiling of KIs we also perform iterative target re-identification of drug candidates during the early drug discovery phase thus providing tools for pharmacology profiling. Using our kinase inhibitor library for the selected survival factor kinase targets, with biochemical kinase assays we identified several potent hit and lead compounds and generated joint pharmacophores. With cellular kinase and proliferation/apoptotic assays we selected potent multiple target drug candidate lead molecules