Studies on New Steroidal Saponins from Allii macrostemonis Bulbus and Their Antitumor Activities Design and Synthesis of Novel Bispecific Molecules for InducingBRD4 Protein Degradation

doi:10.1007/s40242-018-7272-5

Chemical Research in Chinese Universities ›› 2018, Vol. 34 ›› Issue (1): 67-74.doi: 10.1007/s40242-018-7272-5

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Studies on New Steroidal Saponins from Allii macrostemonis Bulbus and Their Antitumor Activities Design and Synthesis of Novel Bispecific Molecules for InducingBRD4 Protein Degradation

WANG Shihui¹, SONG Yuming², WANG Yue¹, GAO Yang¹, YU Shanshan¹, ZHAO Qianqian¹, JIN Xiangqun¹, LU Haibin¹

1. College of Pharmacy, Jilin University, Changchun 130021, P. R. China;
2. China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China

Received:2017-08-17 Online:2018-02-01 Published:2018-01-20
Contact: JIN Xiangqun,E-mail:jingxq@jlu.edu.cn;LU Haibin,E-mail:haibin1025@163.com E-mail:jingxq@jlu.edu.cn;haibin1025@163.com
Supported by:
Supported by the Science and Technology Development Plan Projects of Jilin Province, China(No.20170311057YY).

Abstract

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.

Key words: Proteolysis targeting chimera(PROTAC), Bromodomain-containing protein 4(BRD4) degrader, Bromodomain-containing protein 4(BRD4) inhibitor

WANG Shihui, SONG Yuming, WANG Yue, GAO Yang, YU Shanshan, ZHAO Qianqian, JIN Xiangqun, LU Haibin. Studies on New Steroidal Saponins from Allii macrostemonis Bulbus and Their Antitumor Activities Design and Synthesis of Novel Bispecific Molecules for InducingBRD4 Protein Degradation[J]. Chemical Research in Chinese Universities, 2018, 34(1): 67-74.

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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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