WB-214(WB-214) - 药物靶点：GSPT1 x MDM2_在研适应症：白血病_专利_临床

概要

基本信息

药物类型

分子胶

别名

靶点

GSPT1 x MDM2

作用机制

GSPT1抑制剂(G1 to S phase transition 1 inhibitors)、MDM2抑制剂(p53结合蛋白Mdm-2抑制剂)

治疗领域

肿瘤血液及淋巴系统疾病

在研适应症

白血病

非在研适应症-

原研机构

University of Wisconsin

在研机构

University of Wisconsin

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 WB-214 相关的临床结果

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100 项与 WB-214 相关的转化医学

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100 项与 WB-214 相关的专利（医药）

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1

项与 WB-214 相关的文献（医药）

2021-07-01·European Journal of Medicinal Chemistry1区 · 医学

Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries

1区 · 医学

Article

作者: Teng, Peng ; Tang, Weiping ; Wang, Bo ; Wu, Suzhen ; Tandon, Ira ; Liao, Jianhua ; Liu, Jin

Proteolysis targeting chimeras (PROTACs) have gained tremendous interest in both the academic and pharmaceutical communities. This opens a new way to regulate the cellular protein homeostasis, especially for disease-related proteins. In this work, we designed and synthesized a series of MDM2 degraders based on ligands that were readily prepared by a four-component Ugi reaction. After extensive optimization based on anti-proliferation and MDM2 degradation, WB214 was identified as the most potent anti-proliferative agent in various leukemia cell lines. Surprisingly, our mechanistic investigations indicated that WB214 not only effectively induced the degradation of MDM2, but also led to the degradation of p53. Further studies revealed that WB214 degraded MDM2 as a molecular glue. WB214 and its related analogues did not bind to MDM2 in the p53 binding region and MDM2 was discovered as a novel neo-substrate of the E3 ligase cereblon. Finally, we found that WB214 could potently degrade GSPT1, which could rationalize the inhibition of cell growth. A selective degrader for GSPT1 over MDM2 was then developed through systematically varying different motifs.

100 项与 WB-214 相关的药物交易

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