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：
8877462
负责人：
MARILYN D RESH
金额：
$ 19.13万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8877462
关键词：
Acyltransferase Animals Apoptosis Back Biogenesis Biological Assay Biological Availability Breast Cancer Cell Cancer Cell Growth Cancer Etiology Carbon Cell Proliferation Cessation of life Clinical Trials Cytology Data Drug Kinetics Enzymes Epithelial Cells Erinaceidae Estrogen receptor positive Fatty Acids Generations Genetically Engineered Mouse Goals Growth Health Human In Vitro Infusion Pumps Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Memorial Sloan-Kettering Cancer Center Modeling Molecular Monitor Mus Palmitates Pancreas Paracrine Communication Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacology Proteins Reagent Research SKI gene Services Signal Pathway Signal Transduction Signaling Molecule Sonic Hedgehog Pathway Structure-Activity Relationship Therapeutic Therapeutic Agents Transducers Western Blotting Work Xenograft Model antitumor agent autocrine base cancer cell design high throughput screening human SMO protein in vitro Assay in vivo inhibitor/antagonist malignant breast neoplasm mouse model neoplastic cell novel palmitoylation pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis paracrine pharmacophore research study small molecule smoothened signaling pathway tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：拟议的研究的目的是开发治疗试剂，以阻止Sonic Hedgehog（SHH）信号传导。异常SHH表达与胰腺癌有关，胰腺癌是美国与癌症相关死亡的第四个主要原因。为了发出信号，必须通过将脂肪酸棕榈酸酯附着在其N末端来修饰SHH。我们旨在通过靶向HHAT（刺猬酰基转移酶）来利用SHH棕榈酰化为潜在的致命弱点，该酶是催化棕榈酸盐附着在SHH上的酶。我们的实验室使用高吞吐量筛选来鉴定Ru-Ski 43，这是一种新型的，第一类的小分子HHAT抑制剂，可阻止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。我们旨在将HHAT抑制剂进一步发展为有效治疗胰腺和其他癌症的新型化学治疗剂。该提议还挑战了胰腺癌中的SHH作用仅限于对基质的旁分泌信号传导的教条。我们有数据表明胰腺肿瘤细胞确实确实对SHH做出了反应，但是通过非规范，平滑的独立途径。目前在临床试验中的所有SHH途径抑制剂的目标平滑。拟议的R21项目有可能通过将焦点重新引入肿瘤的靶标，从而为治疗剂设定新的方向上皮细胞。目标1。优化HHAT抑制剂以调节SHH棕榈酰化和信号传导 HHAT抑制剂的作用机理将通过监测胰腺癌细胞中由HHAT和SHH调节的信号通路以及在雌激素受体阳性乳腺癌细胞中确定。接下来，我们将努力优化新的第二代HHAT抑制剂，这些抑制剂比Ru-Ski 43高70倍，在抑制体外抑制SHH Palmitoylation方面，但体内半脂肪均短。由药物和合成化学家开发的结构活性关系和药效团模型将用于第三代以及HHAT抑制剂的合理设计和合成，其效力和生物利用度增加。这些抑制剂的功效将在体外评估人类胰腺癌细胞的SHH棕榈酰化，SHH信号传导和生长。目标2。HHAT抑制剂作为治疗剂，以阻止体内SHH驱动的癌症通过评估化合物的药代动力学和药效动力学（ADME/PK/TOX），该目标中的实验将致力于优化HHAT抑制剂到动物中的递送。评估HHAT抑制剂在胰腺癌的小鼠异种移植模型以及K-Rasg12d/p53R172H小鼠中阻断肿瘤发生的能力，这是一种基因工程胰腺癌的小鼠模型。