DD-01. Ligand and Structure-Based Virtual Screening to Discover Polypharmacological Dual EGFR and BRD4 Inhibitors

publication · 1 year ago
by Stephan Schurer, Saurabh Mehta, Nagi Ayad, Bryce Allen (University of Miami)
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Combination therapy is the standard-of-care for many cancer patients. The standard treatment for Glioblastoma Multiforme (GBM) includes surgical resection, followed by radiotherapy, and temozolomide (TMZ) subministration. However, resistance to TMZ is nearly universal and tumor recurrence is inevitable. Thus, it is desirable to identify effective combination therapies for the treatment of GBM and other aggressive cancers. Recently, bromodomain-containing protein 4 (BRD4) is emerging as an interesting target for drug development for a large number of diseases that are caused by aberrant acetylation of lysine residues, among these cancer. We propose to overcome this problem by generating kinase inhibitors, which also inhibit epigenetic enzymes. We describe a virtual screening approach to identify compounds that are likely to inhibit both BRD4 and epidermal growth factor receptor beta (EGFR) using in silico analysis, docking, and laplacian based modifieralgorithmstopredictrelativeligand-receptordynamics. Keyelements of this approach include algorithmic prediction of EGFR inhibition based on chemical similarity and quantitative structure activity relationships, protein-ligand docking from crystal structure analysis and preparation, and substructure queries to compile a set of commercially available compounds that can be ordered for in vitro assays. We will confirm inhibitory activity of BRD4 by selected compounds via an AlphaLisa Bromodomain-Aceylated Histone H4 Interaction Assay. Of 108 hits from the docking study, 24 compounds were se- lected for validation. Our preliminary results show promising activity of one compound from our AlphaScreen Assay. We will be testing the efficacy of these drugs in patient derived cancer cells in the near future. With this approach, we can unveil new properties of compounds that can inhibit both BRD4 and EGFR. We also show the validation of our chemoinformatic pipeline, which can be used for additional drug discovery efforts and to further explore the field of polypharmacology.

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