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
- 来源:
- 关键词:AddressAmino Acid SubstitutionAmino AcidsBiochemicalBiologicalBiological AssayCancer BiologyCase StudyCell Cycle ArrestCell NucleusCell ProliferationCell SurvivalCellsChemicalsCollectionColon CarcinomaComplexDataDevelopmentDoseFluorescence Resonance Energy TransferFutureGenetic TranscriptionGenomicsGluesGoalsImpairmentIntuitionLeadLibrariesMADH3 geneMADH4 geneMalignant NeoplasmsMalignant neoplasm of pancreasMediator of activation proteinMissense MutationMissionMonitorMutateMutationOncogenicOncologyPathway interactionsPerformancePharmaceutical ChemistryPhaseRecurrenceResearchResolutionScientistSeriesSignal PathwaySignal TransductionSpecificityStructureSubgroupSuppressor MutationsTestingTherapeuticTherapeutic InterventionTimeTransforming Growth Factor betaTriageTumor Suppressor GenesTumor Suppressor ProteinsValidationWorkanaloganti-canceranticancer activityassay developmentbasecancer cellcell growthcheminformaticscolon cancer cell linedruggable targetexperienceextracellulargastrointestinalhigh throughput screeninglead optimizationloss of functionmutantneglectnovelprecision drugsprecision oncologyprotein protein interactionresponsescaffoldscreeningsmall moleculesmall molecule librariessmall molecule therapeuticssuccesstumor
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
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{{ 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:
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