JA-310(JA-310) - 药物靶点：STK24_在研适应症：肿瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

STK24

作用机制

STK24调节剂(serine/threonine kinase 24 modulators)

治疗领域

肿瘤

在研适应症

肿瘤

非在研适应症-

原研机构

Johann Wolfgang Goethe-Universität Frankfurt am Main

在研机构

Johann Wolfgang Goethe-Universität Frankfurt am Main

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C17H19N7O

InChIKeyXBWKVZHZUZNMJE-UHFFFAOYSA-N

CAS号3022928-90-8

关联

100 项与 JA-310 相关的临床结果

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100 项与 JA-310 相关的转化医学

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100 项与 JA-310 相关的专利（医药）

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1

项与 JA-310 相关的文献（医药）

2024-01-11·Journal of Medicinal Chemistry1区 · 医学

Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3

1区 · 医学

Article

作者: Berger, Lena Marie ; Frischkorn, Julia Marie ; Amrhein, Jennifer Alisa ; Krämer, Andreas ; Müller, Susanne ; Kaiser, Astrid ; Elson, Lewis ; Joerger, Andreas C ; Hanke, Thomas ; Berger, Benedict-Tilman ; Knapp, Stefan ; Balourdas, Dimitrios-Ilias ; Menge, Amelie ; Schubert-Zsilavecz, Manfred

MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 (EC₅₀ = 106 nM) and excellent kinome-wide selectivity. The crystal structure of the MST3-JA310 complex provided intriguing insights into the binding mode, which is associated with large-scale structural rearrangements. In summary, JA310 demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents the first chemical probe for MST3.

100 项与 JA-310 相关的药物交易

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