Discovery of small molecule mutant SMAD4-PPI inducers

小分子突变体 SMAD4-PPI 诱导剂的发现

基本信息

  • 批准号:
    10298220
  • 负责人:
  • 金额:
    $ 35.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Tumor suppressor genes represent a major class of oncogenic “drivers” and offer robust window for therapeutic intervention. However, direct targeting loss-of-function tumor suppressor genes remains challenging, because that majority of tumor suppressors do not have enzymatic activity and exert their normal function through protein- protein interaction (PPI). Noteworthy, a unique class of tumor suppressor mutations are missense mutations encoding single amino acid substitutions that impair the normal PPI. These tumor suppressor mutations are defined as “loss-of-interaction” mutation. We aim to directly target the “loss-of-interaction” tumor suppressor mutations through discovery of small molecule PPI inducers to restore their anticancer functions. SMAD4 is such a tumor suppressor with “loss-of-interaction” mutations in cancer that disrupt its normal PPI with SMAD3. Using SMAD4 as a proof-of-concept study, we propose to utilize our newly developed TR-FRET SMAD4-SMAD3 PPI screening platform to reveal novel small molecule mutant SMAD4-PPI inducer (MuSMADid) that can induce the mutant SMAD4 PPI with SMAD3 and restore the pathway and cellular response to the tumor suppressive TGF-b signaling. Preliminary studies showed that the SMAD4-SMAD3 TR-FRET assay is robust and scalable in 1536-well uHTS format and is sensitive to monitor the SMAD4-SMAD3 PPI dynamic at single amino acid resolution. From a bioactive chemical library, Ro-31-8220, a bisindolylmaleimide derivative, was identified as potential MuSMADid that induced the mutant SMAD4 PPI with SMAD3 and restored the responsiveness of SMAD4 mutant colon cancer cells to the TGF-b anti-proliferation signaling. Identification of Ro-31-8220 as a potential MuSMADid provides strong evidence for direct targeting “loss-of-interaction” SMAD4 mutations. Together, this preliminary data supports our central premise that novel chemical probes can be discovered as potential MuSMADid by leveraging the established uHTS TR-FRET assay to screen structurally diverse chemical libraries. Based on the stages of discovery research, our proposal will focus on Aim 1 “Primary Screen Implementation” to identify MuSMADid hits with new chemical scaffolds, followed by verification with orthogonal PPI assays, and on Aim 2 “Functional Validation” to prioritize a list of validated novel small molecule anti-tumor MuSMADid for future hit-to-lead optimization phase. We will use the uHTS TR-FRET platform to rapidly identify primary hits and validated hits followed by characterization of their PPI induction and cellular activities in restoring the TGF-b tumor suppressive signaling. Accomplishing the goals of the proposed study is anticipated to generate a list of prioritized and confirmed small molecule MuSMADid compounds that show potent biochemical and biological activities in inducing the mutant SMAD4-SMAD3 PPI and restoring the TGF-b anti-proliferation signaling pathways. Top ranked anti-tumor MuSMADid with the strongest structural and functional evidence will be used as chemical probes to study the mutant SMAD4-dependent cancer biology and as candidates for future hit-to-lead studies towards the development of novel small molecule MuSMADid drug for precision oncology.
总结 肿瘤抑制基因代表了一类主要的致癌"驱动因子",并为肿瘤的治疗提供了强大的窗口。 干预然而,直接靶向功能丧失的肿瘤抑制基因仍然具有挑战性,因为 大多数肿瘤抑制因子不具有酶活性,而是通过蛋白质- 蛋白质相互作用(PPI)。值得注意的是,一类独特的肿瘤抑制突变是错义突变 编码损害正常PPI的单个氨基酸取代。这些肿瘤抑制基因突变是 定义为"相互作用丧失"突变。我们的目标是直接靶向"失去相互作用"的肿瘤抑制因子 通过发现小分子PPI诱导剂来恢复其抗癌功能。SMAD 4就是这样 一种在癌症中具有"失去相互作用"突变的肿瘤抑制因子,其通过SMAD3破坏其正常PPI。使用 SMAD4作为概念验证研究,我们建议使用我们新开发的TR-FRET SMAD4-SMAD3 PPI 筛选平台,以揭示可以诱导新的小分子突变体SMAD4-PPI诱导剂(MuSMADid), 突变体SMAD4 PPI与SMAD3结合,并恢复对肿瘤抑制的途径和细胞应答。 TGF-β信号传导。初步研究表明,SMAD4-SMAD3 TR-FRET测定法是稳健的和可扩展的, 1536-良好的uHTS格式,并且对监测单个氨基酸处的SMAD4-SMAD3 PPI动态是敏感的 分辨率从生物活性化学文库中,Ro-31 - 8220,一种双吲哚基马来酰亚胺衍生物,被鉴定为 潜在的MuSMADid诱导突变SMAD4 PPI与SMAD3,并恢复 SMAD4突变结肠癌细胞对TGF-β的抗增殖信号。Ro-31 - 8220鉴别为 潜在的MuSMADid为直接靶向"失去相互作用"的SMAD4突变提供了强有力的证据。 总之,这些初步数据支持了我们的中心假设,即可以发现新的化学探针, 通过利用已建立的uHTS TR-FRET测定筛选结构多样的化学物质, 图书馆.根据发现研究的阶段,我们的建议将侧重于目标1 "初步筛选 实施",以确定MuSMADid命中与新的化学支架,然后验证与正交 PPI测定,以及目标2 "功能验证",以优先考虑经验证的新型小分子抗肿瘤药物列表 MuSMADid用于未来的点击率到领先优势优化阶段。我们将使用uHTS TR-FRET平台快速识别 主要命中和验证命中,然后表征其PPI诱导和细胞活性, TGF-β肿瘤抑制信号。实现拟议研究的目标预计将产生 列出了优先考虑和确认的小分子MuSMADid化合物,这些化合物显示出有效的生物化学和 诱导突变SMAD4-SMAD3 PPI和恢复TGF-β抗增殖的生物活性 信号通路具有最强结构和功能证据的顶级抗肿瘤MuSMADid将 作为化学探针研究突变SMAD 4依赖的癌症生物学,并作为未来的候选人, 针对开发用于精确肿瘤学的新型小分子MuSMADid药物的命中领先研究。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Xiulei Mo其他文献

Xiulei Mo的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Xiulei Mo', 18)}}的其他基金

Discovery of small molecule mutant SMAD4-PPI inducers
小分子突变体 SMAD4-PPI 诱导剂的发现
  • 批准号:
    10665612
  • 财政年份:
    2021
  • 资助金额:
    $ 35.79万
  • 项目类别:
Discovery of small molecule mutant SMAD4-PPI inducers
小分子突变体 SMAD4-PPI 诱导剂的发现
  • 批准号:
    10458066
  • 财政年份:
    2021
  • 资助金额:
    $ 35.79万
  • 项目类别:

相似海外基金

Phenotypic consequences of a modern human-specific amino acid substitution in ADSL
ADSL 中现代人类特异性氨基酸取代的表型后果
  • 批准号:
    24K18167
  • 财政年份:
    2024
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Estimation of stability and functional changes due to amino acid substitution using molecular simulations
使用分子模拟估计氨基酸取代引起的稳定性和功能变化
  • 批准号:
    20H03230
  • 财政年份:
    2020
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Elucidation of the mechanisms of prion protein conversion caused by an amino acid substitution in glycosylphosphatidylinositol anchoring signal peptide
阐明糖基磷脂酰肌醇锚定信号肽中氨基酸取代引起的朊病毒蛋白转化机制
  • 批准号:
    16K18790
  • 财政年份:
    2016
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Amino acid substitution without genetic modification
无需基因改造的氨基酸替代
  • 批准号:
    15H05491
  • 财政年份:
    2015
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Young Scientists (A)
Study on PSII hydrogen bond networks by exhaustive amino acid substitution
穷举氨基酸取代研究PSII氢键网络
  • 批准号:
    15K07110
  • 财政年份:
    2015
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Elucidation of the effect of HCV propagationa and IFN sensitivity by amino acid substitution in interferon sensitivity-determining region.
阐明干扰素敏感性决定区氨基酸取代对 HCV 传播和干扰素敏感性的影响。
  • 批准号:
    26860309
  • 财政年份:
    2014
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
The analysis of the restriction of amino acid substitution on the hemagglutinin molecule of influenza A virus
甲型流感病毒血凝素分子氨基酸取代限制性分析
  • 批准号:
    14370104
  • 财政年份:
    2002
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Changes in the Substrate Specificities of Farnesyl Diphosphate Synthase by a Single Amino Acid Substitution
单一氨基酸取代对法尼基二磷酸合酶底物特异性的变化
  • 批准号:
    12680587
  • 财政年份:
    2000
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Analyses of the Relationship between Amino Acid Substitution and Phenotype of the Tail Sheath Protein of Bacteriophage T4
噬菌体T4尾鞘蛋白氨基酸取代与表型关系分析
  • 批准号:
    02680125
  • 财政年份:
    1990
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
Hypothesis: Both appearance and disappearance of viruses are controlled by the accumulation of amino acid substitution in receptor binding domain
假设:病毒的出现和消失都是由受体结合​​域氨基酸取代的积累控制的
  • 批准号:
    02454184
  • 财政年份:
    1990
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了