Studies on New Steroidal Saponins from Allii macrostemonis Bulbus and Their Antitumor Activities Design and Synthesis of Novel Bispecific Molecules for InducingBRD4 Protein Degradation |
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Authors: | WANG Shihui SONG Yuming WANG Yue GAO Yang YU Shanshan ZHAO Qianqian JIN Xiangqun LU Haibin |
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Affiliation: | 1. College of Pharmacy, Jilin University, Changchun 130021, P. R. China;
2. China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China |
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Abstract: | Proteolysis targeting chimeras(PROTACs) are bispecific molecules containing a target protein binder and a ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4(BRD4) degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of (9.4±0.6) nmol/L. Furthermore, compound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of (27.6±1.6) nmol/L and capable of inducing degradation of BRD4 protein at 0.5―1.0 μmol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader. |
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Keywords: | Proteolysis targeting chimera(PROTAC) Bromodomain-containing protein 4(BRD4) degrader Bromodomain-containing protein 4(BRD4) inhibitor |
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