Bromodomain-Selective BET Inhibitors Are Potent Antitumor Agents against MYC-Driven Pediatric Cancer.

Autor:	Slavish PJ; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Chi L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Yun MK; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Tsurkan L; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Martinez NE; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Jonchere B; Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Chai SC; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Connelly M; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Waddell MB; Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee., Das S; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Neale G; Hartwell Center, St. Jude Children's Research Hospital, Memphis, Tennessee., Li Z; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Shadrick WR; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Olsen RR; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Freeman KW; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee., Low JA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Price JE; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Young BM; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Bharatham N; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Boyd VA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Yang J; Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee., Lee RE; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Morfouace M; Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Roussel MF; Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Chen T; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., Savic D; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee., Guy RK; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee., White SW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee., Shelat AA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee. phil.potter@stjude.org anang.shelat@stjude.org., Potter PM; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee. phil.potter@stjude.org anang.shelat@stjude.org.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Sep 01; Vol. 80 (17), pp. 3507-3518. Date of Electronic Publication: 2020 Jul 10.
DOI:	10.1158/0008-5472.CAN-19-3934
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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