Optimization and Characterization of "MYC Degraders" for Pediatric Medulloblastoma
Optimization and Characterization of "MYC Degraders" for Pediatric Medulloblastoma
批准号:
10612251
负责人:
Michael Jackson
金额:
$48.75万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-15 至 2023-04-30
关键词:
AffectAntineoplastic AgentsBioinformaticsBiological AssayBiological MarkersBromodomainCell SurvivalCellsChemicalsChemotherapy and/or radiationChildChildhoodChildhood Brain NeoplasmChildhood MedulloblastomasCollectionDataDevelopmentDiagnosisDiseaseExhibitsFrequenciesGene ExpressionGenetic MarkersGenetic TranscriptionGenomicsGoalsHourHumanIncidenceInduced pluripotent stem cell derived neuronsLeadLibrariesMYC Family ProteinMYC geneMalignant NeoplasmsMalignant neoplasm of cerebellumMetabolicMolecular ProfilingMonitorMusMutationOncoproteinsOperative Surgical ProceduresPatient-Focused OutcomesPatientsPermeabilityPharmaceutical ChemistryPhasePhenotypePropertyProtein phosphataseRadiationRecurrenceRouteSHH geneSamplingSeriesSolubilityStructure-Activity RelationshipSubgroupSurvival RateSurvivorsTestingTherapeuticTherapeutic AgentsTimeToxic effectanalogaurora kinase Abiomarker signatureblood-brain barrier penetrationc-myc Geneschemotherapydesigndrug discoverydruggable targeteffective therapyexperimental studyimmunohistochemical markersimprovedin vivoin vivo evaluationinhibitorlead optimizationmedulloblastomamolecular markermouse modelnovelnovel therapeuticsoverexpressionpatient derived xenograft modelpharmacokinetics and pharmacodynamicspre-clinicalprotein activationscaffoldscale upside effectsmall moleculetargeted treatmenttherapeutically effectivetreatment grouptumortumor growth
中文摘要
项目总结
英文摘要
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.
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