Drug Repurposing by Connectivity Mapping and Structural Modeling

Here, we will describe a combinatorial approach for drug discovery using two technologies—genomic connectivity mapping (C-MAPping) and structural modeling—to repurpose drugs, using bisphosphonates as a paradigm. Bisphosphonates are the mainstay of therapy for the skeletal fragility associated with aging, menopause, cancer, and chronic inflammatory diseases. Using mRNA microarrays, we generated a gene signature of bisphosphonate action on human osteoclasts. Interrogation of the Connectivity Map (C-MAP) identified potential bisphosphonate mimetics, which included 1,5-isoquinolinediol, a PARP inhibitor, and tyrphostin AG1478, an inhibitor of human EGFR (HER). In silico modeling suggested that bisphosphonates, due to a similarity of chemical structure to pyrophosphate, could bind to the kinase domain of the EGFR. Confirmatory in vitro testing showed a potent inhibition of osteoclast formation in vitro with the two agents, respectively. This was accompanied by reduced Akt phosphorylation, also suggesting increased apoptosis. Additionally, consistent with previous results, bisphosphonates attenuated EGF-induced cell proliferation of EGFR-overexpressing non-small cell lung cancer cells (H1666), and reduced cell viability of those driven by a known activating mutation, namely EGFR△E746-A750 (HCC827). Thus, C-MAP together with computational modeling not only allowed us to discover bisphosphonate-like, osteoprotective actions of two anticancer drugs, but more importantly prompted studies on the use of bisphosphonates for EGFR-driven cancers.