Characterization of novel pyrazole compounds with potent anti-cancer activity
具有有效抗癌活性的新型吡唑化合物的表征
基本信息
- 批准号:10627543
- 负责人:
- 金额:$ 15.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAfrican AmericanAnimalsAntibodiesAntineoplastic AgentsAsianBCL1 OncogeneBasic ScienceBiochemicalBiological AssayBreastBreast Cancer CellBreast Cancer cell lineCASP3 geneCancer EtiologyCancer cell lineCaspaseCause of DeathCell Death InductionCell LineCell membraneCellsCessation of lifeClinical TrialsCombination Drug TherapyCountryDNA FragmentationDataDatabasesDiagnosisDockingDrug ScreeningExhibitsFDA approvedFamilyFutureGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGoalsHispanicHumanHypoxiaImmunotherapyImplantInduction of ApoptosisLatinaLeukemic CellLibrariesLuc GeneLuciferasesMDA MB 231Malignant NeoplasmsMinority GroupsMitochondriaMolecular TargetMonitorMusNamesNetwork-basedPathway interactionsPharmaceutical PreparationsPharmacotherapyPhosphorylationPhosphotransferasesProtein KinaseProteinsPyrazolesReactive Oxygen SpeciesReverse Transcriptase Polymerase Chain ReactionRoleSignal TransductionSignal Transduction PathwaySmall Interfering RNATestingTherapeutic AgentsTranslatingTumor Suppressor GenesUnited States National Institutes of HealthWestern BlottingWomanXenograft Modelanaloganti-canceranti-cancer therapeuticanticancer activitybioluminescence imagingcancer cellcancer health disparitycancer typecytotoxicdifferential expressioneffective therapyexperimental studyhigh riskin silicoin vivoinhibitorkinase inhibitorknock-downleukemialive cell imagingmalignant breast neoplasmnovelnovel anticancer drugscreeningstable cell linetimelinetranscriptometranscriptome sequencingtranscriptomic profilingtriple-negative invasive breast carcinomatumortumor diagnosistumor growthtumor progression
项目摘要
Breast cancer is the most frequently diagnosed tumor type and a common cause of cancer-related
deaths in women worldwide. In the US, African American (AA) and Hispanic/Latina women exhibit a
higher proportion of Triple Negative Breast Cancer (TNBC) than White or Asian women. In addition,
AA women have a higher risk of dying from, and being diagnosed with TNBC. Since TNBC is an
aggressive subtype with no available molecular targets and lack of immunotherapy, we have focused
our recent drug screens to identify compounds that are cytotoxic against these cells. Using a live-cell
imaging screening assay developed by my group, we recently screened 4,600 novel compounds from
the Chembridge DIVERset drug-like library of compounds on the MDA-MB-231 TNBC line and
detected fifteen compounds with significant cytotoxic activity against these cells. The most potent of
the compounds (a pyrazole-3-carbohydrazyde named P3C) was subsequently evaluated on additional
cancer cell lines and found to be cytotoxic to most cancer cell lines. A recent search for structural
analogues of P3C resulted in the identification of a compound (P3C.1) with stronger anti-cancer
activity than the original. Although P3C and P3C.1 have similar cytotoxic activity on a variety of cancer
cell lines, they also differ in activity on a small subset of cell lines. Our data indicate that they both
induce apoptosis via increased reactive oxygen species, mitochondrial depolarization, caspase
activation, cell membrane disruption, and DNA fragmentation. However, our preliminary results
indicate that the pyrazoles activate distinct signal transduction pathways. Our central hypothesis is
that the identified pyrazoles induce apoptosis via distinct pathways. Therefore, the main objective of
this project is to determine the mode of action (MOA) of each compound by comparing their gene
expression profiles and effects on key signal transduction pathways. Understanding the MOA of these
compounds is critical when testing compounds in clinical trials and in drug combination therapy. In
addition, an important goal of this proposal is to determine if the compounds reduce/inhibit tumor
progression in mice implanted with human tumors with the hope of eventually translating this basic
research into effective anticancer therapeutics that can help reduce cancer health disparities.
乳腺癌是最常被诊断的肿瘤类型,也是与癌症相关的常见病因
项目成果
期刊论文数量(0)
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{{ truncateString('RENATO J AGUILERA', 18)}}的其他基金
G-RISE at the University of Texas at El Paso
德克萨斯大学埃尔帕索分校的 G-RISE
- 批准号:
10361081 - 财政年份:2022
- 资助金额:
$ 15.14万 - 项目类别:
U-RISE at the University of Texas at El Paso
德克萨斯大学埃尔帕索分校的 U-RISE
- 批准号:
10597695 - 财政年份:2022
- 资助金额:
$ 15.14万 - 项目类别:
G-RISE at the University of Texas at El Paso
德克萨斯大学埃尔帕索分校的 G-RISE
- 批准号:
10594456 - 财政年份:2022
- 资助金额:
$ 15.14万 - 项目类别:
U-RISE at the University of Texas at El Paso
德克萨斯大学埃尔帕索分校的 U-RISE
- 批准号:
10412416 - 财政年份:2022
- 资助金额:
$ 15.14万 - 项目类别:
Characterization of novel compounds with anti-lymphoma activity
具有抗淋巴瘤活性的新型化合物的表征
- 批准号:
8414350 - 财政年份:2013
- 资助金额:
$ 15.14万 - 项目类别:
Characterization of novel compounds with anti-lymphoma activity
具有抗淋巴瘤活性的新型化合物的表征
- 批准号:
8870385 - 财政年份:2013
- 资助金额:
$ 15.14万 - 项目类别:
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