2. Academic Validation
  3. Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies

Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies

  • Bioorg Med Chem. 2020 Jan 1;28(1):115181. doi: 10.1016/j.bmc.2019.115181.
Fei Jiang 1,  Qingyun Wei 2,  Huili Li 3,  Hongmei Li 3,  Yong Cui 3,  Yu Ma 3,  Haifang Chen 3,  Peng Cao 4,  Tao Lu 5,  Yadong Chen 6
Affiliations

Affiliations

  • 1 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, PR China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China.
  • 3 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 4 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, PR China; Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China. Electronic address: [email protected].
  • 5 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
  • 6 School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 31767403 DOI: 10.1016/j.bmc.2019.115181
Abstract

The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and Cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers.

Keywords

BRD4 and BRD2; Cancers; PROTAC degraders; Selectivity.

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