SBIR TOPIC 255, PHASE I: DEVELOPMENT OF ANTICANCER VATPASE INHIBITORS

SBIR 主题 255，第一阶段：抗癌 VATP 酶抑制剂的开发

• 批准号: 8352539
• 负责人: DONALD STEWART
• 金额: $ 19.99万
• 依托单位: OMM SCIENTIFIC, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8352539
• 关键词: Acidity; Alcohols; Antineoplastic Agents; Brain; Budgets; Buffers; Businesses; Carbamates; Carboxylic Acids; Cessation of life; Clinic; Clinical; Clinical Drug Development; Clinical Trials; Continuous Infusion; Contracts; Data; Development; Development Plans; Diamines; Dose; Doxorubicin; Drug Kinetics; Drug resistance; Environment; Esters; Ethylenes; Funding; Glutamates; Half-Life; High Pressure Liquid Chromatography; Hour; Hydrolysis; In Vitro; Isotonic Exercise; Lead; Liver; Malignant Neoplasms; Methods; Modeling; Modification; Mus; Neoplasm Metastasis; Outcome; Paclitaxel; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Phenotype; Plasma; Polymers; Process; Prodrugs; Property; Publishing; Pump; Research Personnel; Resistance; Safety; Site; Small Business Innovation Research Grant; Sodium; Sodium Chloride; Testing; Therapeutic Agents; TimeLine; Toxic effect; Xenograft procedure; anticancer activity; arm; base; chemical stability; design; drug candidate; efficacy testing; experience; hydroxyl group; improved; in vivo; inhibitor/antagonist; innovation; inorganic phosphate; male; malignant breast neoplasm; meetings; melanoma; neurotoxicity; pantothenate; polyglutamate; pre-clinical; tumor; tumor growth; vacuolar H+-ATPase

Invasive, metastatic, and/or drug resistant cancers are responsible for most cancer deaths. Development of a drug that blocks these phenotypes to improve outcomes is the ultimate objective. The specific means is by inhibiting the acidification of extra-cellular and extra-tumoral environments that otherwise facilitates invasion, metastasis, and drug resistance. The lead, RD203, potently inhibits the V-ATPase pump largely responsible for acidification and shows compelling anticancer activities. However, it requires continuous infusion for in vivo efficacy, an impediment to further development. Synthesis and testing of prod rugs of RD203 that mimic the exposure and compelling in vivo efficacy of continuous infusion is the challenging innovation and overall objective of this proposal. RD203 will be synthesized and used to prepare several types of each of three classes of prod rugs designed to release free RD203 slowly and/or target release at the tumor site. The modifications were selected for safety, develop-ability, and precedence in previous clinical development. The prodrugs will be screened and winnowed down by testing for useful: (a) chemical stability, (b) MTD, (c) desired pharmacokinetic profile, and (d) in vivo efficacy with daily doses. From this process one or two RD203 prodrugs will be selected for further development. Provide

浸润性、转移性和/或耐药癌症是大多数癌症死亡的原因。开发一种 阻断这些表型以改善结果的药物是最终目标。具体的手段是通过 抑制细胞外和肿瘤外环境的酸化，否则会促进侵袭， 转移和耐药。铅RD203在很大程度上抑制了V-ATPase泵 用于酸化，并显示出令人信服的抗癌活性。然而，它需要持续输液才能 活体效应，阻碍进一步发展。 RD203模拟暴露和体内药效的Prod地毯的合成和测试 持续输液是这项提议具有挑战性的创新和总体目标。RD203将成为 合成并用于制备三类生产地毯中的每一种的几种类型，旨在免费释放 RD203在肿瘤部位缓慢和/或靶向释放。选择改装是为了安全起见， 开发能力，在以往的临床开发中具有优先地位。将对前药进行筛选和 通过测试筛选出有用的：(A)化学稳定性，(B)MTD，(C)所需的药代动力学曲线，以及 (D)每日剂量的体内疗效。从这一过程中，将选择一到两种RD203前药用于进一步 发展。 提供