title: Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4.
abstract: Inhibition of cancer-promoting kinases is an established therapeutic strategy for the treatment of many cancers, although resistance to kinase inhibitors is common. One way to overcome resistance is to target orthogonal cancer-promoting pathways. Bromo and Extra-Terminal (BET) domain proteins, which belong to the family of epigenetic readers, have recently emerged as promising therapeutic targets in multiple cancers. The development of multitarget drugs that inhibit kinase and BET proteins therefore may be a promising strategy to overcome tumor resistance and prolong therapeutic efficacy in the clinic. We developed a general computational screening approach to identify novel dual kinase/bromodomain inhibitors from millions of commercially available small molecules. Our method integrated machine learning using big datasets of kinase inhibitors and structure-based drug design. Here we describe the computational methodology, including validation and characterization of our models and their application and integration into a scalable virtual screening pipeline. We screened over 6 million commercially available compounds and selected 24 for testing in BRD4 and EGFR biochemical assays. We identified several novel BRD4 inhibitors, among them a first in class dual EGFR-BRD4 inhibitor. Our studies suggest that this computational screening approach may be broadly applicable for identifying dual kinase/BET inhibitors with potential for treating various cancers.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, US.|Center for Computational Science, University of Miami, Miami, FL, US.|Center for Therapeutic Innovation Miller School of Medicine, University of Miami, Miami, FL, US.|Miami Project to Cure Paralysis, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, US.
authors.forename: Bryce K
authors.initials: BK
authors.lastname: Allen
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, US.|Center for Computational Science, University of Miami, Miami, FL, US.|Department of Applied Chemistry, Delhi Technological University, Delhi, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, US.
authors.forename: Stewart W J
authors.initials: SW
authors.lastname: Ember
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, US.
authors.forename: Ernst
authors.initials: E
authors.lastname: Schonbrunn
authors.affiliation: Center for Therapeutic Innovation Miller School of Medicine, University of Miami, Miami, FL, US.|Miami Project to Cure Paralysis, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, US.
authors.forename: Nagi
authors.initials: N
authors.lastname: Ayad
authors.affiliation: Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, US.|Center for Computational Science, University of Miami, Miami, FL, US.|Center for Therapeutic Innovation Miller School of Medicine, University of Miami, Miami, FL, US.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schürer
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D018797:Cell Cycle Proteins; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D000069550:Machine Learning; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D059467:Transcriptome; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C512478:EGFR protein, human