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

• 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
• 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

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）：拟定研究的总体目标是确定将我们的新型GGDPS特异性抑制剂用于治疗骨髓瘤和骨转移性疾病的临床开发的可行性。许多这些新的不含氮的双膦酸盐，最值得注意的是LWS-138，表现出超过领先的商业替代品的特异性，使它们成为进一步开发临床用途的有利候选物。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允许对我们在初步工作中确定的三种潜在的先导化合物中的每一种进行/不进行决定。我们计划为这些研究制备足够的铅系列中的每一个成员（4-5克）。我们将同时进行定量测定细胞培养基、细胞裂解物和小鼠血浆中每种候选物的方法开发和验证。主要可行性研究将需要结合代谢、膜渗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中的体内疗效研究。从这些研究中，我们将优先考虑在更复杂的转移性骨疾病模型中进一步研究的化合物，作为第二阶段提案的一部分。据估计，2005年将有大约500 000例新的乳腺癌、前列腺癌或多发性骨髓瘤诊断，当年死于这些癌症的人数将达到82 000人。几乎所有在疾病进展中介于这两个点之间的患者都会在某个时候出现转移性骨病。局限于骨骼的转移性疾病与内脏转移相比预期寿命更长相关，但也具有显著的发病率;因此，可以降低这一大组患者发病率的新疗法显然将使公众受益。