Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 2, Pages 462-481Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01816
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Funding
- Breast Cancer Research Foundation
- University of Michigan Comprehensive Cancer Center Strategic Fund for Breast Cancer
- University of Michigan Comprehensive Cancer Center Core Grant from the National Cancer Institute, NIH [P30CA046592]
- Medsyn Biopharma
- NATIONAL CANCER INSTITUTE [P30CA046592] Funding Source: NIH RePORTER
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The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic readers and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
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