Chemotherapeutic Agents with Enhanced Selectivity for the Tumor Microenvironment

对肿瘤微环境具有增强选择性的化疗药物

• 批准号: 8627137
• 负责人: Kevin G. Pinney
• 金额: $ 27.45万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627137
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adherence; Affect; Aftercare; Antibodies; Antineoplastic Agents; Area; Binding; Biochemical; Biological; Biological Assay; Bioluminescence; Blood Vessels; Blood flow; Breast Adenocarcinoma; Breast Cancer Cell; Cancer cell line; Carboplatin; Cell Culture Techniques; Cell Line; Cells; Cellular Morphology; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Combined Modality Therapy; Combretastatin A-4; Combretastatin A4 Phosphate; Coupled; DU145; Development; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Event; Exhibits; Feedback; Fibronectins; Fluorescence; GTP Binding; Gadolinium; Goals; Growth; Growth Factor; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Histology; Housing; Human; Hydrochloride Salt; Image; Image Analysis; Immunofluorescence Immunologic; In Vitro; Individual; Indoles; Inhibitory Concentration 50; Investigation; Label; Laboratories; Lead; Left; Luciferases; MDA MB 231; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mediating; Medical center; Methods; Microtubule Depolymerization; Microtubule stabilizing agent; Microtubules; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Morphology; Movement; Mus; National Cancer Institute; Nature; Necrosis; Nutrient; Ovarian Carcinoma; Oxygen; Paclitaxel; Pentetic Acid; Perfusion; Peripheral; Pharmaceutical Chemistry; Pharmacodynamics; Play; Positioning Attribute; Procedures; Prodrugs; Prostate carcinoma; Protocols documentation; Public Health; Relative (related person); Research; Residual Tumors; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; Role; Route; Saline; Salts; Serum; Signal Transduction; Small Interfering RNA; Structure; Techniques; Texas; Time; Translating; Treatment Efficacy; Tube; Tubular formation; Tubulin; Tubulin Binding Agent; Umbilical vein; United States Food and Drug Administration; Universities; Validation; Variant; Vascular Endothelial Growth Factors; Vascular blood supply; Water; Western Blotting; Work; Xenograft Model; Xenograft procedure; analog; angiogenesis; base; bioluminescence imaging; cancer therapy; cancer type; cell growth; chemical synthesis; chemotherapeutic agent; chemotherapy; clinically relevant; clinically significant; cytotoxicity; density; design; feeding; fluorescence microscope; functional group; gadolinium oxide; improved; in vivo; in vivo imaging; innovation; inorganic phosphate; interdisciplinary approach; kinase inhibitor; knock-down; light emission; lung Carcinoma; matrigel; neoplastic cell; new growth; novel; polymerization; preclinical study; prevent; programs; public health relevance; research study; rho; rho GTP-Binding Proteins; rhotekin; screening; success; tissue oxygenation; tool; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): The discovery and development of new treatment agents for cancer that demonstrate enhanced selectivity for the tumor microenvironment continues to be an important and challenging goal in today's world. Vascular disrupting agents (VDAs) are compounds that are effective at selectively damaging the tumor vasculature while leaving the blood supply to healthy cells intact. These compounds effectively disrupt blood flow to tumors thus starving them of necessary nutrients and oxygen. This has the potential to ultimately lead to tumor death. While a number of VDAs are in human clinical trials, none have reached approval by the Food and Drug Administration (FDA), to date. Certain of these compounds function by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature. This triggers a cascade of cell signaling events that results in catastrophic damage to the vessels feeding the tumor. The research presented in this proposal focuses on a highly collaborative, multidisciplinary approach to the synthesis and rapid biological evaluation of promising new VDAs. A combination of synthetic/medicinal chemistry to prepare newly designed compounds coupled with rapid biochemical and biological evaluation, including tumor imaging (BLI and MRI), will provide a strong platform for the discovery of new and improved VDAs. Importantly, this type of research may ultimately translate to the clinic providing additional chemotherapeutic agents that have enhanced selectivity towards the tumor microenvironment.

描述（由申请人提供）：发现和开发对肿瘤微环境具有增强选择性的新型癌症治疗药物仍然是当今世界重要且具有挑战性的目标。血管破坏剂（VDA）是有效地选择性破坏肿瘤血管系统同时保持健康细胞的血液供应完整的化合物。这些化合物有效地破坏了流向肿瘤的血液，从而使它们缺乏必要的营养和氧气。这有可能最终导致肿瘤死亡。虽然许多VDA正在进行人体临床试验，但迄今为止还没有一种获得食品和药物管理局（FDA）的批准。这些化合物中的某些化合物通过抑制微管蛋白组装成微管而起作用，从而引起肿瘤血管系统内衬的内皮细胞的形态学变化。这引发了一系列细胞信号事件，导致对肿瘤供血血管的灾难性损害。本提案中提出的研究重点是高度协作的多学科方法，以合成和快速生物学评价有前途的新VDAs。合成/药物化学的组合，以制备新设计的化合物，再加上快速的生化和生物学评价，包括肿瘤成像（BLI和MRI），将为发现新的和改进的VDA提供一个强大的平台。重要的是，这种类型的研究可能最终转化为临床，提供对肿瘤微环境具有增强选择性的额外化疗药物。

项目成果

Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.

生物还原性可激活的苯他汀前药缀合物，旨在针对肿瘤缺氧。

• DOI: 10.1016/j.bmcl.2016.11.093
• 发表时间: 2017
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Winn,BlakeA;Shi,Zhe;Carlson,GrahamJ;Wang,Yifan;Nguyen,BensonL;Kelly,EvanM;Ross4th,RDavid;Hamel,Ernest;Chaplin,DavidJ;Trawick,MaryL;Pinney,KevinG
• 通讯作者: Pinney,KevinG

Mechanistic Considerations in the Synthesis of 2-Aryl-Indole Analogues under Bischler-Mohlau Conditions.

Bischler-Mohlau 条件下合成 2-芳基-吲哚类似物的机理考虑。

• DOI: 10.1016/j.tetlet.2015.01.129
• 发表时间: 2015
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: MacDonough,MatthewT;Shi,Zhe;Pinney,KevinG
• 通讯作者: Pinney,KevinG

An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity.

一种氨基苯并芘烯类似物，可抑制微管蛋白组装并表现出显着的细胞毒性。

• DOI: 10.1039/c2md00318j
• 发表时间: 2012
• 期刊: MedChemComm
• 作者: Tanpure,RajendraP;George,ClintonS;Sriram,Madhavi;Strecker,TracyE;Tidmore,JustinK;Hamel,Ernest;Charlton-Sevcik,AmandaK;Chaplin,DavidJ;Trawick,MaryLynn;Pinney,KevinG
• 通讯作者: Pinney,KevinG

Efficient Synthetic Methodology for the Construction of Dihydronaphthalene and Benzosuberene Molecular Frameworks.

构建二氢萘和苯并芘烯分子框架的高效合成方法。

• DOI: 10.1016/j.tetlet.2018.12.033
• 发表时间: 2019
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Mondal,Deboprosad;Niu,Haichan;Pinney,KevinG
• 通讯作者: Pinney,KevinG