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Targeting the colchicine binding site in tubulin for cancer therapy

靶向微管蛋白中的秋水仙碱结合位点进行癌症治疗

基本信息

批准号：
10298280
负责人：
WEI LI
金额：
$ 40.33万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298280
关键词：
ABCG2 gene Address Affinity Allergic Androgens Binding Binding Sites Cancer Patient Cell Line Clinical Clinical Management Clinical Trials Colchicine Crystallization DU145 Data Daughter Development Disease Dose Dose-Limiting Drug Kinetics Drug resistance Drug usage FDA approved FOLH1 gene Fracture Frequencies Funding Future Generations Goals Grant Hematopoietic Hybrids Immunotherapy In Vitro Indium-111 Lead Length Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Neoplasm Metastasis Neutropenia Oral Pain Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase II Clinical Trials Property Prostate Cancer therapy Prostatic Neoplasms Quality of life Resistance Resolution Roentgen Rays Site Solubility Structure Therapeutic Index Toxic effect Tubulin X-Ray Crystallography Xenograft Model acquired drug resistance analog anti-cancer aqueous base bisphosphonate bone cancer therapy cancer type chemotherapeutic agent chemotherapy clinical candidate clinical efficacy design docetaxel drug candidate efficacious treatment efficacy study improved in vivo in vivo Model inhibitor/antagonist mortality nerve damage neurotoxicity next generation novel therapeutics overexpression patient derived xenograft model phase II trial phase III trial prostate cancer cell line prostate cancer metastasis prostate cancer model pyrrolidin-3-yl-methanesulfonic acid resistance mechanism scaffold side effect spinal cord compression success surfactant targeted agent targeted treatment taxane triple-negative invasive breast carcinoma tumor

项目摘要

Despite recent advances in both targeted therapy and immunotherapy, the overall survival (OS) for metastatic prostate cancer (PCa) remains low. This renewal application is to continue our productive efforts to develop a new tubulin inhibitor that can overcome drug resistance associated with FDA approved tubulin inhibitors, and will therefore, increase OS in PCa and other types of cancers where anti-tubulin drugs are used. The support from the previous periods of funding has resulted in a new drug candidate, Veru-111, which is under Phase 2 clinical trials for metastatic PCa. While Veru-111 is on a promising path to gain future FDA approval, there are significant room for improvement. The goals of this renewal are: (1) to develop the next generation of Veru-111 to proactively address its anticipated drug resistance; and (2) to develop targeted Veru- 111 drug conjugates to increase drug accumulation in prostate tumors and to target PCa bone metastasis. Aim 1. Develop a new generation of Veru-111, that can overcome both taxane resistance and the anticipated Veru-111 resistance. Preliminary data: We have discovered a hybrid scaffold based on Veru-111 and Azixa, represented by SHIP-216, that can overcome resistances to both taxanes and Veru-111. Approaches: Guided by high-resolution X-ray crystal structures, we will optimize the SHIP-216 scaffold to further improve its potency and drug-like properties. New analogs will be evaluated against a panel of PCa cell lines, including both taxane- and Veru-111-resistant cell lines to select the best five analogs for in vivo efficacy studies in Aim 3. Aim 2. Conjugate Veru-111 with PSMA targeting moieties to increase drug accumulation in PCa tumors and conjugate Veru-111 with bisphosphonates for more efficacious targeting of bone metastasis. Preliminary data: we have demonstrated Veru-111 itself can significantly reduce bone metastasis in a PDX model. We have also developed linkers for conjugating Veru-111 with PSMA targeting moieties or bisphosphonates. Approaches: we will optimize the length and composition of the linkers to PSMA targeting moieties and use different bisphosphonates in conjugation, to generate focused sets of Veru-111 drug conjugates. These conjugates will be first evaluated in vitro for stability and activation to select the best four conjugates (two in PMSA and two in bisphosphonates conjugates) for further in vivo efficacy studies in Aim 3. Aim 3. We will determine the maximum tolerable dose (MTD), pharmacokinetics (PK), and in vivo efficacy of the selected nine compounds from Aims 1-2 in both PCa cell line models and a PDX model to select the overall best compound to support subsequent clinical trials in the Veru-111 portfolio. Preliminary data: we have already shown that SHIP-216 as a new Veru-111 analog is highly efficacious against multiple xenograft models, including the 22Rv1 PCa and the Veru-111 resistant DU-145/VxR PCa models. Approaches: We will evaluate all selected new compounds for their designed ability to treat prostate tumors using both cell line and PDX models in vivo.

尽管最近在靶向治疗和免疫治疗方面都取得了进展，但转移性前列腺癌（PCa）仍然很低。这次更新申请是为了继续我们富有成效的努力，开发一种新的微管蛋白抑制剂，可以克服FDA批准的微管蛋白相关的耐药性抑制剂，因此将增加PCa和使用抗微管蛋白药物的其他类型癌症的OS。前几期资金的支持产生了一种新的候选药物Veru-111，转移性前列腺癌的2期临床试验虽然Veru-111有望获得未来的FDA批准，批准，有很大的改进余地。这次更新的目标是：（1）开发下一个 Veru-111的产生，以积极解决其预期的耐药性;（2）开发靶向Veru-111， 111药物缀合物以增加前列腺肿瘤中的药物积累并靶向PCa骨转移。目标1。开发新一代Veru-111，既能克服紫杉烷耐药性，预计Veru-111耐药性。初步数据：我们发现了一种基于Veru-111的混合支架和Azixa，以SHIP-216为代表，可以克服对紫杉烷和Veru-111的抗性。方法：在高分辨率X射线晶体结构的指导下，我们将优化SHIP-216支架，以进一步改善其效力和药物样性质。新的类似物将针对一组PCa细胞系进行评估，包括两者紫杉烷和Veru-111抗性细胞系，以选择最佳的五种类似物用于Aim 3中的体内功效研究。目标2.将Veru-111与PSMA靶向部分缀合以增加PCa中的药物蓄积肿瘤和缀合Veru-111与二膦酸盐更有效地靶向骨转移。初步数据：我们已经证明Veru-111本身可以显著减少PDX模型中的骨转移。我们还开发了用于将Veru-111与PSMA靶向部分或双膦酸盐缀合的接头。方法：我们将优化PSMA靶向部分的接头的长度和组成，并使用不同的双膦酸盐缀合，以产生集中的Veru-111药物缀合物组。这些首先在体外评价缀合物的稳定性和活化性， PMSA和二膦酸盐缀合物中的两种）用于目的3中的进一步体内功效研究。目标3。我们将确定最大耐受剂量（MTD）、药代动力学（PK）和体内试验。在PCa细胞系模型和PDX模型中，从目的1-2选择的九种化合物对选择整体最佳化合物，以支持Veru-111产品组合的后续临床试验。初步数据：我们已经表明，SHIP-216作为一种新的Veru-111类似物，多个异种移植物模型，包括22 Rv 1 PCa和Veru-111抗性DU-145/GTR PCa模型。方法：我们将评估所有选定的新化合物治疗前列腺肿瘤的设计能力在体内使用细胞系和PDX模型。