Hedgehog Acyltransferase as a target in cancer
Hedgehog 酰基转移酶作为癌症靶标
基本信息
- 批准号:8748493
- 负责人:
- 金额:$ 22.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcyltransferaseAnimalsApoptosisBackBiogenesisBiological AssayBiological AvailabilityBreast Cancer CellCancer Cell GrowthCancer EtiologyCarbonCell ProliferationCessation of lifeClinical TrialsCytologyDataDrug KineticsEnzymesEpithelial CellsErinaceidaeEstrogen receptor positiveFatty AcidsGenerationsGenetically Engineered MouseGoalsGrowthHumanIn VitroInfusion PumpsLaboratoriesMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMediatingMemorial Sloan-Kettering Cancer CenterModelingMolecularMonitorMusPalmitatesPancreasParacrine CommunicationPathway interactionsPharmaceutical PreparationsPharmacodynamicsPharmacologyProteinsReagentResearchSKI geneServicesSignal PathwaySignal TransductionSignaling MoleculeSonic Hedgehog PathwayStructure-Activity RelationshipTherapeuticTherapeutic AgentsTransducersWestern BlottingWorkXenograft Modelantitumor agentautocrinebasecancer celldesignhigh throughput screeninghuman SMO proteinin vitro Assayin vivoinhibitor/antagonistmalignant breast neoplasmmouse modelneoplastic cellnovelpalmitoylationpancreatic cancer cellspancreatic neoplasmpancreatic tumorigenesisparacrinepharmacophorepublic health relevanceresearch studysmall moleculesmoothened signaling pathwaytumortumor growthtumorigenesis
项目摘要
The goal of the proposed research is to develop therapeutic reagents to block signaling by Sonic
hedgehog (Shh). Aberrant Shh expression is implicated in pancreatic cancer, the 4th leading cause of
cancer-related deaths in the US. In order to signal, Shh must be modified by attachment of the fatty acid
palmitate to its N-terminus. We aim to exploit Shh palmitoylation as a potential Achilles heel by targeting
Hhat (Hedgehog acyltransferase), the enzyme that catalyzes attachment of palmitate to Shh. Our
laboratory used high throughput screening to identify RU-SKI 43, a novel, first-in-class small molecule
Hhat inhibitor that blocks Shh palmitoylation, autocrine and paracrine Shh signaling, and human
pancreatic cancer cell growth. We aim to further develop Hhat inhibitors into novel chemotherapeutics
efficacious for the treatment of pancreatic and other cancers.
This proposal also challenges the dogma that Shh action in pancreatic cancer is limited to
paracrine signaling to the stroma. We have data that pancreatic tumor cells do indeed respond to Shh but
via non-canonical, Smoothened-independent pathways. All of the Shh pathway inhibitors currently in
clinical trials target Smoothened. The proposed R21 project has the potential to set a new direction in
therapeutics by bringing the focus back to targets in the tumor epithelial cells.
Aim 1. Optimization of Hhat inhibitors to regulate Shh palmitoylation and signaling
The mechanism of action of Hhat inhibitors will be determined by monitoring signaling pathways
regulated by Hhat and Shh in pancreatic cancer cells, as well as in estrogen-receptor positive breast
cancer cells. Next, we will work on optimizing new, 2nd generation Hhat inhibitors that are up to 70x more
potent than RU-SKI 43 in inhibiting Shh palmitoylation in vitro, but have short in vivo half-lives. Structure-
activity relationships and a pharmacophore model developed by medicinal and synthetic chemists will be
used for rational design and synthesis of 3rd generation and beyond Hhat inhibitors with increased potency
and bioavailability. The efficacy of these inhibitors for blocking Shh palmitoylation, Shh signaling and
growth of human pancreatic cancer cells in vitro will be assessed.
Aim 2. Hhat inhibitors as therapeutic agents to block Shh-driven cancers in vivo
Experiments in this aim will be devoted to optimizing delivery of Hhat inhibitors into animals, by
assessing pharmacokinetics and pharmacodynamics (ADME/PK/TOX) of the compounds. The ability of
Hhat inhibitors to block tumorigenesis in a mouse xenograft model of pancreatic cancer, as well as in K-
RasG12D/p53R172H mice, a genetically engineered mouse model of pancreatic cancer, will be assessed.
拟议研究的目标是开发治疗试剂来阻断 Sonic 信号传导
刺猬(嘘)。 Shh 表达异常与胰腺癌有关,胰腺癌是导致胰腺癌的第四大原因
美国癌症相关死亡。为了发出信号,Shh 必须通过连接脂肪酸进行修饰
棕榈酸酯连接至其 N 末端。我们的目标是利用 Shh 棕榈酰化作为潜在的致命弱点
Hhat(Hedgehog 酰基转移酶),一种催化棕榈酸附着到 Shh 上的酶。我们的
实验室使用高通量筛选来鉴定 RU-SKI 43,一种新型的一流小分子
Hhat 抑制剂可阻断 Shh 棕榈酰化、自分泌和旁分泌 Shh 信号传导以及人类
胰腺癌细胞的生长。我们的目标是进一步将 Hhat 抑制剂开发成新型化疗药物
对治疗胰腺癌和其他癌症有效。
该提案还挑战了胰腺癌中“嘘”作用仅限于的教条
向基质发出旁分泌信号。我们有数据表明胰腺肿瘤细胞确实对“嘘”有反应,但是
通过非规范的、平滑的独立路径。目前所有的Shh通路抑制剂
临床试验目标平滑。拟议的 R21 项目有可能为以下领域设定新方向:
通过将焦点带回肿瘤上皮细胞中的靶标来进行治疗。
目标 1. 优化 Hhat 抑制剂来调节 Shh 棕榈酰化和信号传导
Hhat抑制剂的作用机制将通过监测信号通路来确定
在胰腺癌细胞以及雌激素受体阳性乳腺癌细胞中受 Hhat 和 Shh 调节
癌细胞。接下来,我们将致力于优化新的第二代 Hhat 抑制剂,其性能提高了 70 倍
在体外抑制 Shh 棕榈酰化方面比 RU-SKI 43 更有效,但体内半衰期较短。结构-
由药物和合成化学家开发的活性关系和药效团模型将
用于合理设计和合成具有增强效力的第三代及以上 Hhat 抑制剂
和生物利用度。这些抑制剂阻断 Shh 棕榈酰化、Shh 信号传导和
将评估人类胰腺癌细胞的体外生长。
目标 2. Hhat 抑制剂作为治疗剂在体内阻断 Shh 驱动的癌症
旨在实现这一目标的实验将致力于优化 Hhat 抑制剂向动物体内的递送,方法是:
评估化合物的药代动力学和药效学 (ADME/PK/TOX)。的能力
Hhat 抑制剂可阻断小鼠胰腺癌异种移植模型以及 K-
将评估 RasG12D/p53R172H 小鼠(一种胰腺癌基因工程小鼠模型)。
项目成果
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{{ truncateString('MARILYN D RESH', 18)}}的其他基金
Fatty Acylation of Hedgehog and Wnt Proteins
Hedgehog 和 Wnt 蛋白的脂肪酰化
- 批准号:
9197314 - 财政年份:2016
- 资助金额:
$ 22.83万 - 项目类别:
Hedgehog Acyltransferase as a target in cancer
Hedgehog 酰基转移酶作为癌症靶标
- 批准号:
8877462 - 财政年份:2014
- 资助金额:
$ 22.83万 - 项目类别:
Hedgehog Palmitoylation as a Novel Target for Inhibiting Pancreatic Cancer
Hedgehog 棕榈酰化作为抑制胰腺癌的新靶点
- 批准号:
8089813 - 财政年份:2011
- 资助金额:
$ 22.83万 - 项目类别:
Hedgehog Palmitoylation as a Novel Target for Inhibiting Pancreatic Cancer
Hedgehog 棕榈酰化作为抑制胰腺癌的新靶点
- 批准号:
8227998 - 财政年份:2011
- 资助金额:
$ 22.83万 - 项目类别:
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