DDO-5994(DDO-5994) - 药物靶点：CDC37 x HSP90_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

CDC37 x HSP90

作用机制

CDC37拮抗剂(cell division cycle 37, HSP90 cochaperone antagonists)、HSP90 抑制剂(Heat shock 90kDa proteins inhibitors)

治疗领域

肿瘤

在研适应症-

非在研适应症

肿瘤

原研机构

上海恒瑞医药有限公司

中国药科大学

在研机构-

非在研机构

中国药科大学

上海恒瑞医药有限公司

最高研发阶段无进展临床前

首次获批日期-

最高研发阶段(中国)无进展

特殊审评-

关联

100 项与 DDO-5994 相关的临床结果

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100 项与 DDO-5994 相关的转化医学

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100 项与 DDO-5994 相关的专利（医药）

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1

项与 DDO-5994 相关的文献（医药）

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

Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core

1区 · 医学

Article

作者: Xu, Xiaoli ; Zhou, Jianrui ; Zhang, Lianshan ; Zhang, Qiuyue ; Wang, Lei ; Zhang, Lixiao ; You, Qidong ; Wu, Xuexuan

HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode of compound 11 (previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (K_D = 5.52 μM) and antiproliferative activity (IC₅₀ = 6.34 μM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.

100 项与 DDO-5994 相关的药物交易

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