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）：拟议研究的目标是开发治疗试剂来阻断刺猬索尼克（Shh）的信号传导。 Shh 表达异常与胰腺癌有关，胰腺癌是美国癌症相关死亡的第四大原因。为了发出信号，Shh 必须通过在其 N 末端连接脂肪酸棕榈酸酯进行修饰。我们的目标是通过针对 Hhat（刺猬酰基转移酶）（一种催化棕榈酸酯与 Shh 附着的酶）来利用 Shh 棕榈酰化作为潜在的致命弱点。我们的实验室使用高通量筛选来鉴定 RU-SKI 43，这是一种新型、一流的小分子 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 抑制剂开发成有效治疗胰腺癌和其他癌症的新型化疗药物。该提议还挑战了“Shh 在胰腺癌中的作用仅限于向基质发出旁分泌信号”的教条。我们有数据表明，胰腺肿瘤细胞确实对Shh做出反应，但通过非规范的、独立于Smoothened的途径。目前处于临床试验中的所有 Shh 通路抑制剂都以 Smoothened 为目标。拟议的 R21 项目有可能通过将焦点带回肿瘤靶点来设定新的治疗方向上皮细胞。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胰腺癌细胞以及雌激素受体阳性乳腺癌细胞中 Hhat 和 Shh 调节的信号通路来确定。接下来，我们将致力于优化新型第二代 Hhat 抑制剂，该抑制剂在体外抑制 Shh 棕榈酰化方面的效力比 RU-SKI 43 强 70 倍，但体内半衰期较短。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合理设计和合成具有更高效力和生物利用度的第三代及以后的 Hhat 抑制剂。将评估这些抑制剂在体外阻断 Shh 棕榈酰化、Shh 信号传导和人胰腺癌细胞生长的功效。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通过评估化合物的药代动力学和药效学 (ADME/PK/TOX) 来优化 Hhat 抑制剂向动物体内的递送。将评估 Hhat 抑制剂在小鼠胰腺癌异种移植模型以及 K-RasG12D/p53R172H 小鼠（一种胰腺癌基因工程小鼠模型）中阻断肿瘤发生的能力。