Optimization and Characterization of "MYC Degraders" for Pediatric Medulloblastoma

小儿髓母细胞瘤“MYC 降解剂”的优化和表征

基本信息

项目摘要

PROJECT SUMMARY Medulloblastoma (MB) is a highly malignant tumor of the cerebellum that occurs most frequently in children. Despite advances in treatment – including surgery, radiation, and chemotherapy – approximately one-third of MB patients still die from the disease and survivors suffer severe side effects as a result of treatment. Genomic profiling and bioinformatic analyses of patient samples have identified four subgroups of MB – WNT, Sonic hedgehog (SHH), Group 3 (MYC-driven) and Group 4. These subgroups differ in terms of mutations, gene expression profiles and patient outcomes, and patients can be stratified using relevant genetic and immunohistochemical markers. Approximately one-quarter of MBs are Group 3 (G3) tumors, which exhibit overexpression or amplification of the c-Myc (MYC) oncogene. Patients with G3 MB are more likely to present with metastatic disease at time of diagnosis, have a higher incidence of recurrence and the poorest survival rate. Thus, more effective therapies for G3 MB are critically needed. To identify MYC inhibitors that would be effective in G3 MB, we developed a phenotypic, target-agnostic assay using disease-relevant cells isolated from G3 MB orthotopic patient-derived xenografts (PDXs). The assay was designed to identify small molecules that reduce endogenous MYC levels – the signature molecular marker of G3 MB – in 4 hours, to preferentially modulate targets directly affecting MYC stability and avoid indirect or off- target effects at later time points. We applied this assay to screen a 100,000 compound collection and identified small molecule scaffolds that robustly decrease cellular MYC levels. Hits were validated in a rigorous testing funnel designed to avoid undesired mechanisms of action, and initial SAR was explored for several scaffolds. From these studies the most promising series was prioritized with activities in the 100 nM potency range as well as compound properties indicative of good BBB penetration. We further confirmed that the compounds in this series decrease cell viability after 48 hours exposure and that this effect correlates with potency in the MYC assay. Preliminary data for the most active compound of this series, SBI1242, indicate that this decrease in cell viability of G3 MB patient cells is selective over iPSC-derived neurons, suggesting a possible therapeutic window. The goal of this proposal is to further optimize SBI1242 for preclinical in vivo testing and use the best analog to test our hypothesis that inhibitors of the G3 MB signature biomarker MYC identified in a highly disease-relevant context can safely and effectively arrest or reverse tumor growth in our G3 MB-specific orthotopic PDX mouse model. We anticipate that successful completion of these studies will be a significant step towards our long-term goal of identifying novel, safe, and effective treatments for MB and other MYC-driven cancers.
项目总结

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 }}

Michael Jackson其他文献

Michael Jackson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('Michael Jackson', 18)}}的其他基金

Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT)
靶向端粒酶逆转录酶 (TERT) 的突变启动子
  • 批准号:
    10677899
  • 财政年份:
    2023
  • 资助金额:
    $ 48.75万
  • 项目类别:
Brain-penetrant GPR88 agonists as novel therapeutics for opioid abuse
脑渗透性 GPR88 激动剂作为阿片类药物滥用的新型疗法
  • 批准号:
    10517225
  • 财政年份:
    2022
  • 资助金额:
    $ 48.75万
  • 项目类别:
Preventing Tau uptake by novel inhibitors of tau binding to LRP1
通过与 LRP1 结合的新型 tau 抑制剂阻止 Tau 摄取
  • 批准号:
    10343473
  • 财政年份:
    2022
  • 资助金额:
    $ 48.75万
  • 项目类别:
Preventing Tau uptake by novel inhibitors of tau binding to LRP1
通过与 LRP1 结合的新型 tau 抑制剂阻止 Tau 摄取
  • 批准号:
    10581565
  • 财政年份:
    2022
  • 资助金额:
    $ 48.75万
  • 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
  • 批准号:
    10183333
  • 财政年份:
    2020
  • 资助金额:
    $ 48.75万
  • 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
  • 批准号:
    10400863
  • 财政年份:
    2020
  • 资助金额:
    $ 48.75万
  • 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
  • 批准号:
    10595660
  • 财政年份:
    2020
  • 资助金额:
    $ 48.75万
  • 项目类别:
A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
  • 批准号:
    10037550
  • 财政年份:
    2020
  • 资助金额:
    $ 48.75万
  • 项目类别:
Developing Choroid Plexus-Based Tools and Drug Screens
开发基于脉络丛的工具和药物筛选
  • 批准号:
    9304373
  • 财政年份:
    2016
  • 资助金额:
    $ 48.75万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8379692
  • 财政年份:
    2012
  • 资助金额:
    $ 48.75万
  • 项目类别:

相似海外基金

Delays in Acquisition of Oral Antineoplastic Agents
口服抗肿瘤药物的获取延迟
  • 批准号:
    9975367
  • 财政年份:
    2020
  • 资助金额:
    $ 48.75万
  • 项目类别:
Eliminate the difficulty of venous puncture in patients receiving antineoplastic agents - Development of a new strategy for the prevention of induration-
消除接受抗肿瘤药物的患者静脉穿刺的困难 - 制定预防硬结的新策略 -
  • 批准号:
    16K11932
  • 财政年份:
    2016
  • 资助金额:
    $ 48.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Molecular mechanisms of the antineoplastic agents inhibiting DNA replication and their applications to cancer patient treatmen
抗肿瘤药物抑制DNA复制的分子机制及其在癌症患者治疗中的应用
  • 批准号:
    19591274
  • 财政年份:
    2007
  • 资助金额:
    $ 48.75万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
PNET EXPERIMENTAL THERAPEUTICS--ANTINEOPLASTIC AGENTS AND TREATMENT DELIVERY
PNET 实验治疗——抗肿瘤药物和治疗实施
  • 批准号:
    6346309
  • 财政年份:
    2000
  • 资助金额:
    $ 48.75万
  • 项目类别:
TRAINING IN PHARMACOLOGY OF ANTINEOPLASTIC AGENTS
抗肿瘤药物药理学培训
  • 批准号:
    2720213
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
TRAINING IN PHARMACOLOGY OF ANTINEOPLASTIC AGENTS
抗肿瘤药物药理学培训
  • 批准号:
    6513197
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
Training in Pharmacology of Antineoplastic Agents
抗肿瘤药物药理学培训
  • 批准号:
    7101017
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
Training in Pharmacology of Antineoplastic Agents
抗肿瘤药物药理学培训
  • 批准号:
    6894842
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
  • 批准号:
    2885074
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
  • 批准号:
    6174221
  • 财政年份:
    1999
  • 资助金额:
    $ 48.75万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了