Inhibitors of Rho function as novel cancer therapeutics

Rho 抑制剂可作为新型癌症疗法

• 批准号: 7624230
• 负责人: SAID M SEBTI
• 金额: $ 114.09万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624230
• 关键词: Inhibitors; Rho; function; novel; cancer

DESCRIPTION (provided by applicant): The overall goals of this NCDDG application is to discover novel anticancer drugs based on inhibiting the aberrant activation of Rho GTPases in human cancer. Aberrant activation of Rho GTPases is associated with tumor invasion, metastasis and poor prognosis. Aberrant activation involves several mechanisms including Rho overexpression (RhoC), alternative splicing (Rac1) or persistent activation of guanine nucleotide exchange factor (RhoGEFs such as the Rac specific GEF Tiam1, and the RhoA/C specific GEF, LARG). Furthermore, persistent activation of Rho GTPases depends on their posttranslational modification by geranylgeranyltransferase 1 (GGTase 1) anci the transforming activity of some Rho GTPases requires the ser/thr kinase Rho kinase (ROCK). The hypothesis upon which this NCDDG is based is that inhibitors of GEFs, GGTase I and RhoK will reverse malignant transformation of cancers with aberrant Rho function. To test this hypothesis we propose 3 complementary and interdependent programs and 2 cores. Program 1 will design, based on available structural information as well as hits from Core B, novel GGTase I, GEF and RHOK inhibitors. Core B will use experimental and virtual high throughput screening (HTS) as well as molecular modeling to identify GGTase I, RhoGEF and ROCK inhibitors. Program 2 will focus on validation and characterization of inhibitors of RhoGEF, GGTase I and RHOK. Program 3 will evaluate the effects of GEF, GGTase I and RHOK inhibitors on Rho signaling and function as well as their antitumor activity, pharmacokinetics and toxicity in animal models. The 3 programs and the 2 cores will work very closely together towards achieving the specific objectives and the overall goal of the NCDDG. These concerted efforts will lead to novel anticancer drugs that will increase the spectrum of human cancers that can be treated by thwarting the aberrant activation of Rho GTPases.

描述（由申请人提供）：NCDDG应用的总体目标是发现基于抑制人类癌症Rho GTPases异常激活的新型抗癌药物。 Rho GTPases的异常激活与肿瘤侵袭，转移和预后不良有关。异常激活涉及多种机制，包括Rho过表达（RHOC），替代剪接（RAC1）或鸟嘌呤核苷酸交换因子的持续激活（RhoGEFS，例如RAC特异性GEF TIAM1和RHOA/C特异性GEF，Larg）。此外，Rho GTPases的持续激活取决于它们通过黄烷基凝血酶1（GGTase 1）ANCI ANCI的翻译后修饰，某些Rho GTP酶的转化活性需要Ser/Thr激酶Rho rho激酶（岩石）。该NCDG所基于的假设是GEF，GGTase I和Rhok的抑制剂将逆转具有异常RHO功能的癌症的恶性转化。为了检验这一假设，我们提出了3个互补和相互依存的程序以及2个核心。程序1将根据可用的结构信息以及核心B，新型GGTase I，GEF和Rhok抑制剂的命中设计设计。核心B将使用实验和虚拟高通量筛选（HTS）以及分子建模来识别GGTase I，Rhogef和Rock抑制剂。计划2将重点介绍Rhogef，GGTase I和Rhok的抑制剂的验证和表征。程序3将评估GEF，GGTase I和Rhok抑制剂对动物模型中RHO信号传导和功能以及它们的抗肿瘤活性，药代动力学和毒性的影响。这3个程序和2个核心将非常紧密地努力实现NCDG的特定目标和整体目标。这些协同的努力将导致新颖的抗癌药物，这些药物将增加人类癌症的范围，这些癌症可以通过挫败Rho GTPases的异常激活来治疗。

项目成果

Targeting protein prenylation for cancer therapy.

• DOI: 10.1038/nrc3151
• 发表时间: 2011-10-24
• 期刊: Nature reviews. Cancer

Borderline resectable pancreatic cancer: on the edge of survival.

• DOI: 10.1177/107327480801500404
• 发表时间: 2008-10
• 期刊: Cancer control : journal of the Moffitt Cancer Center
• 作者: G. Springett;S. Hoffe

Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I.

蛋白质香叶基香叶基转移酶-I 的有效、高选择性、非硫醇抑制剂。

• DOI: 10.1021/jm9900873
• 发表时间: 1999
• 期刊: Journal of medicinal chemistry.
• 作者: Vasudevan,A;Qian,Y;Vogt,A;Blaskovich,MA;Ohkanda,J;Sebti,SM;Hamilton,AD
• 通讯作者: Hamilton,AD

Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors.

• DOI: 10.1021/jm201289r
• 发表时间: 2012-03-08
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Li R;Martin MP;Liu Y;Wang B;Patel RA;Zhu JY;Sun N;Pireddu R;Lawrence NJ;Li J;Haura EB;Sung SS;Guida WC;Schonbrunn E;Sebti SM
• 通讯作者: Sebti SM

Effects of structure of Rho GTPase-activating protein DLC-1 on cell morphology and migration.

• DOI: 10.1074/jbc.m800617200
• 发表时间: 2008-11-21
• 期刊: The Journal of biological chemistry
• 作者: Kim TY;Healy KD;Der CJ;Sciaky N;Bang YJ;Juliano RL
• 通讯作者: Juliano RL