Preclinical Development of Geranylgeranyl Disphosphate Synthase Inhibitors as Ant

香叶基香叶基二磷酸合酶抑制剂 Ant 的临床前开发

基本信息

批准号：
7325831
负责人：
JEFFREY D NEIGHBORS
金额：
$ 12.31万
依托单位：
TERPENOID THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7325831
关键词：
Affinity Ants Area Behavior Biological Markers Biological Models Bone Diseases Breast Calibration Cancer Model Cancer Patient Caspase Cell Membrane Permeability Cells Cessation of life Class Clinical Culture Media Data Development Disease Disease Progression Drug Kinetics Enzymes Exhibits Feasibility Studies Geranyltranstransferase Goals High Pressure Liquid Chromatography Hydroxyl Radical In Vitro Lead Life Expectancy Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Metabolism Methodology Modeling Molecular Morbidity - disease rate Movement Multiple Myeloma Mus Neoplasm Metastasis Nitrogen Numbers Osteoclasts Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Phase Pilot Projects Plasma Plasma Proteins Pre-Clinical Model Prostate Protein Binding Protein Geranylgeranylation Protein Inhibition Protocols documentation Reporting Research Secure Series Skeletal system Skeleton Specificity Statistically Significant Therapeutic Thinking Time Tissues Validation Visceral Work Xenograft Model Xenograft procedure bisphosphonate breast cancer diagnosis cancer cell cellular targeting cytotoxicity design dosage farnesyltranstransferase human disease improved in vitro Model in vivo inhibitor/antagonist intraperitoneal isoprenoid liquid chromatography mass spectrometry member metabolic abnormality assessment method development novel pre-clinical subcutaneous therapy development tumor

项目摘要

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to establish the feasibility of moving our novel class of GGDPS specific inhibitors into clinical development for treatment of myeloma and metastatic disease of the bone. The specificity that a number of these novel non-nitrogen- containing bisphosphonates, most notably LWS-138, exhibit over the leading commercial alternatives makes them favorable candidates for further development aimed at clinical usage. Phase One of this project contains four specific aims designed to prove feasibility of this premise. These aims are formulated to allow a go/no-go decision on each of three potential lead compounds we have identified in our preliminary work. We plan to make enough of each member of our lead series for these studies (4-5 grams). We will concurrently carry out method development and validation for quantitative determination of each of these candidates in cell culture media, cell lysate, and mouse plasma. The primary feasibility studies will entail a combination of in vitro pharmacokinetic studies of metabolism, membrane permeability, and plasma protein binding; and in vivo efficacy studies in mouse xenograft breast and prostate cancer models. From these studies we will prioritize the compounds for further study in more elaborate models of metastatic bone disease as part of a Phase Two proposal. It was estimated that there would be approximately 500,000 new diagnoses of cancers of the breast, prostate or multiple myeloma in 2005, and that deaths from these cancers in that year would reach a total of 82,000. Nearly all of the patients who are somewhere between these two points in the disease progression will present with metastatic bone disease at some time. Metastatic disease confined to the skeleton is associated with a longer life expectancy than visceral metastasis but also with significant morbidity; therefore new therapies which could lessen the morbidity in this large group of patients would clearly benefit the public.

描述（由申请人提供）：拟议研究的总体目标是确定将我们的新型 GGDPS 特异性抑制剂转移到治疗骨髓瘤和骨转移性疾病的临床开发中的可行性。许多此类新型非含氮双膦酸盐（尤其是 LWS-138）相对于领先的商业替代品表现出的特异性，使其成为针对临床应用进一步开发的有利候选者。该项目的第一阶段包含四个具体目标，旨在证明这一前提的可行性。制定这些目标是为了对我们在初步工作中确定的三种潜在先导化合物中的每一种做出是否进行的决定。我们计划为这些研究提供足够的先导系列的每个成员（4-5 克）。我们将同时进行方法开发和验证，以定量测定细胞培养基、细胞裂解物和小鼠血浆中的每种候选物。主要可行性研究将需要结合代谢、膜通透性和血浆蛋白结合的体外药代动力学研究；以及小鼠异种移植乳腺癌和前列腺癌模型的体内功效研究。作为第二阶段提案的一部分，我们将根据这些研究优先考虑这些化合物，以便在更精细的转移性骨疾病模型中进行进一步研究。据估计，2005年将有大约50万新诊断出乳腺癌、前列腺癌或多发性骨髓瘤，当年死于这些癌症的人数将达到82,000人。几乎所有处于疾病进展过程中的这两点之间的患者都会在某个时间出现转移性骨病。局限于骨骼的转移性疾病比内脏转移具有更长的预期寿命，但也具有显着的发病率；因此，能够降低这一大群患者发病率的新疗法显然将使公众受益。