RT Journal Article
SR Electronic
T1 Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 3507
OP 3518
DO 10.1158/0008-5472.CAN-19-3934
VO 80
IS 17
A1 Slavish, P. Jake
A1 Chi, Liying
A1 Yun, Mi-Kyung
A1 Tsurkan, Lyudmila
A1 Martinez, Nancy E.
A1 Jonchere, Barbara
A1 Chai, Sergio C.
A1 Connelly, Michele
A1 Waddell, M. Brett
A1 Das, Sourav
A1 Neale, Geoffrey
A1 Li, Zhenmei
A1 Shadrick, William R.
A1 Olsen, Rachelle R.
A1 Freeman, Kevin W.
A1 Low, Jonathan A.
A1 Price, Jeanine E.
A1 Young, Brandon M.
A1 Bharatham, Nagakumar
A1 Boyd, Vincent A.
A1 Yang, Jun
A1 Lee, Richard E.
A1 Morfouace, Marie
A1 Roussel, Martine F.
A1 Chen, Taosheng
A1 Savic, Daniel
A1 Guy, R. Kiplin
A1 White, Stephen W.
A1 Shelat, Anang A.
A1 Potter, Philip M.
YR 2020
UL http://cancerres.aacrjournals.org/content/80/17/3507.abstract
AB 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.