McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
基本信息
- 批准号:8593797
- 负责人:
- 金额:$ 15.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-07 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAntineoplastic AgentsApoptoticBindingBiological MarkersBreast Cancer CellBreast Cancer ModelBreast Cancer TreatmentCell Death ProcessCell ProliferationCell SurvivalCellsClinicClinical TrialsDefectDevelopmentDrug TargetingGene AmplificationGeneticHumanInstructionMaintenanceMalignant NeoplasmsMammary NeoplasmsMetabolismMethodsMolecular GeneticsMutationMyeloid CellsNormal tissue morphologyPatientsPharmacologic SubstancePropertyProteinsReportingResistanceSignal TransductionStructureTestingVirulentbasebreast tumorigenesischemotherapydesignin vivoinhibitor/antagonistleukemiamalignant breast neoplasmneoplastic cellnoveloverexpressionpre-clinicalpro-apoptotic proteinrestorationsmall moleculetriple-negative invasive breast carcinomatumortumor initiation
项目摘要
instnjctions):
Amplification of the gene encoding the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is a common
genetic aberration in breast cancer. Mcl-1 overexpression in human cancers is associated with high tumor
grade, resistance to chemotherapy and poor patient survival. Preclinical evidence suggests that Mcl-1 is a
promising target for the treatment of breast cancers including the highly aggressive triple negative breast
cancer (TNBC) subtype. Although attempts to target Mcl-1 have been reported, compounds specifically
targeting Mcl-1 have not entered the clinic. Using a combination of fragment-based methods and structure-
based design, we have discovered novel small molecules that bind to Mcl-1 with high affinity (KD - 35 nM) for
the BH3-binding pocket, the motif used by Mcl-1 to bind to and sequester pro-apoptotic proteins. Therefore, we
hypothesize that targeted inhibition of Mcl-1 will result in restoration of apoptotic signaling and increased
sensitivity to chemotherapy in Mcl-1-dependent breast tumors. To test this hypothesis, we propose the
following specific aims:
Aim 1. Discover potent (sub-nanomolar) and specific Mcl-1 inhibitors using fragment-based methods and
structure-based design
Aim 2. Optimize potent Mcl-1 inhibitors for their cell-based activities, pharmaceutical properties and In vivo
efficacy in breast cancer models
Aim 3. Identify genetic and molecular biomarkers of sensitivity to Mcl-1 inhibition, alone or in combination with
other anticancer agents with a focus in TNBC
RELEVANCE (See instructions):
Preclinical evidence suggests Mcl-1 is a common genetic alteration in breast cancer, including the virulent
TNBC subtype. Development of rational and novel targeted drugs against this subtype of breast cancer is a
major unmet need. We propose herein a translational project aimed at developing a potent and specific Mcl-1
inhibitor that will be ready for clinical trials within 5 years.
实例):
扩增编码抗凋亡蛋白髓系细胞白血病-1(Mcl-1)的基因是一种常见的
乳腺癌中的基因突变。MCL-1在人类肿瘤中的过度表达与高肿瘤相关
分级高,对化疗耐药,患者存活率低。临床前证据表明Mcl-1是一种
治疗乳腺癌的有希望的靶点,包括高度侵袭性的三阴性乳房
癌症(TNBC)亚型。尽管针对Mcl-1的尝试已有报道,但化合物特别是
靶向Mcl-1尚未进入临床。使用基于片段的方法和结构的组合-
在设计的基础上,我们发现了与McL-1高亲和力(KD-35 nm)结合的新型小分子
BH3结合口袋,Mcl-1用来结合和隔离促凋亡蛋白的基序。因此,我们
假设靶向抑制Mcl-1将导致细胞凋亡信号的恢复和增加
Mcl-1依赖性乳腺肿瘤对化疗的敏感性。为了检验这一假设,我们提出了
以下是具体目标:
目的1.使用基于片段的方法发现有效的(亚纳米分子)和特异的Mcl-1抑制剂
基于结构的设计
目的2.优化有效的Mcl-1抑制剂的细胞活性、药学特性和体内试验
乳腺癌模型的疗效观察
目的3.确定对Mcl-1抑制敏感的遗传和分子生物标记物,单独或与
其他抗癌药物在TNBC中的重点
相关性(请参阅说明):
临床前证据表明,Mcl-1是乳腺癌中一种常见的基因突变,包括恶性
TNBC亚型。针对这一亚型乳腺癌的合理和新型靶向药物的开发是一项
未得到满足的主要需求。我们在此提出了一个翻译项目,旨在开发一种有效和特异的Mcl-1
将在5年内准备进行临床试验的抑制剂。
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)
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Rebecca Sara Cook其他文献
Rebecca Sara Cook的其他文献
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{{ truncateString('Rebecca Sara Cook', 18)}}的其他基金
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10596246 - 财政年份:2021
- 资助金额:
$ 15.36万 - 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10737831 - 财政年份:2021
- 资助金额:
$ 15.36万 - 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10445055 - 财政年份:2021
- 资助金额:
$ 15.36万 - 项目类别:
In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy
原位白蛋白结合 siRNA 用于三阴性乳腺癌肿瘤穿透和分子靶向治疗
- 批准号:
10661771 - 财政年份:2021
- 资助金额:
$ 15.36万 - 项目类别:
McI-1 Inhibitors for the treatment of Breast Cancer
用于治疗乳腺癌的 MCI-1 抑制剂
- 批准号:
8764759 - 财政年份:2014
- 资助金额:
$ 15.36万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8196980 - 财政年份:2009
- 资助金额:
$ 15.36万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8591383 - 财政年份:2009
- 资助金额:
$ 15.36万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
7768523 - 财政年份:2009
- 资助金额:
$ 15.36万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
7998156 - 财政年份:2009
- 资助金额:
$ 15.36万 - 项目类别:
HER3 Signaling in Development and Cancer of the Breast
乳腺癌发育和癌症中的 HER3 信号转导
- 批准号:
8390510 - 财政年份:2009
- 资助金额:
$ 15.36万 - 项目类别:
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