Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer
| Autor: | Barbara Jonchere, Jonathan Low, Michele Connelly, Liying Chi, Sergio C. Chai, R. Kiplin Guy, Kevin W. Freeman, Brandon Young, Jeanine E. Price, Mi-Kyung Yun, Marie Morfouace, Anang A. Shelat, Geoffrey Neale, Rachelle R. Olsen, Nagakumar Bharatham, Daniel Savic, Stephen W. White, P. Jake Slavish, Vincent A. Boyd, Lyudmila Tsurkan, Jun J. Yang, Nancy E. Martinez, Zhenmei Li, Martine F. Roussel, Philip M. Potter, M. Brett Waddell, William R. Shadrick, Richard E. Lee, Taosheng Chen, Sourav Das |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Antineoplastic Agents Context (language use) Mice SCID Article Proto-Oncogene Proteins c-myc Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Protein Domains Cell Line Tumor Neoplasms Neuroblastoma medicine Animals Humans Child Cytotoxicity Oncogene Chemistry Cancer medicine.disease Xenograft Model Antitumor Assays Pediatric cancer Bromodomain 030104 developmental biology Oncology Drug development Drug Design 030220 oncology & carcinogenesis Cancer research Female Transcription Factors |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-19-3934 |
| Popis: | Inhibition of members of the bromodomain and extraterminal (BET) family of proteins has proven a valid strategy for cancer chemotherapy. All BET identified to date contain two bromodomains (BD; BD1 and BD2) that are necessary for recognition of acetylated lysine residues in the N-terminal regions of histones. Chemical matter that targets BET (BETi) also interact via these domains. Molecular and cellular data indicate that BD1 and BD2 have different biological roles depending upon their cellular context, with BD2 particularly associated with cancer. We have therefore pursued the development of BD2-selective molecules both as chemical probes and as potential leads for drug development. Here we report the structure-based generation of a novel series of tetrahydroquinoline analogs that exhibit >50-fold selectivity for BD2 versus BD1. This selective targeting resulted in engagement with BD-containing proteins in cells, resulting in modulation of MYC proteins and downstream targets. These compounds were potent cytotoxins toward numerous pediatric cancer cell lines and were minimally toxic to nontumorigenic cells. In addition, unlike the pan BETi (+)-JQ1, these BD2-selective inhibitors demonstrated no rebound expression effects. Finally, we report a pharmacokinetic-optimized, metabolically stable derivative that induced growth delay in a neuroblastoma xenograft model with minimal toxicity. We conclude that BD2-selective agents are valid candidates for antitumor drug design for pediatric malignancies driven by the MYC oncogene. Significance: This study presents bromodomain-selective BET inhibitors that act as antitumor agents and demonstrates that these molecules have in vivo activity towards neuroblastoma, with essentially no toxicity. |
| Databáze: | OpenAIRE |
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