Abstract 3690: Ligand- and structure-based virtual screening to discover dual EGFR and BRD4 inhibitors
Authors: Allen Bryce , Mehta Saurabh , Ayad Nagi , Schürer Stephan 
Published: August 2015

Combination therapy is the standard-of-care for many cancer patients. However, for some cancers it is not feasible to identify effective treatments since drug combinations have not been tested.  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. Kinase inhibitors have recently gained attention as effective therapies for the treatment of multiple cancers. However, resistance to kinase inhibitors is very common due to upregulation of compensatory mechanisms that overcome the requirement for the particular kinase being inhibited.   Recent discoveries suggest that the onset and or maintenance of cancer also involve alterations in the “epigenome”, which may cause extensive genomic reprogramming in cancer cells in part mediated by changes in DNA methylation and a variety of histone modifications. The realization that “epigenetic” alteration in cancer may be reversible has led to the identification of novel targets that may result in new strategies for the treatment of cancer. The principal readers of acetylated lysine residues on histones are the bromodomains (BRDs), and they have been implicated in the development of a large variety of diseases. 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 cancers. We propose to overcome this problem by generating kinase inhibitors, which also inhibit epigenetic targets.

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 modifier algorithms to predict relative ligand-receptor dynamics. Key elements 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 selected for validation. Our results show promising activity of one compound from our AlphaScreen Assay.

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.

Citation Format: Bryce Allen, Saurabh Mehta, Nagi Ayad, Stephan Schürer. Ligand- and structure-based virtual screening to discover dual EGFR and BRD4 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2015-3690