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

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

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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.

尽管有针对性的治疗和免疫疗法最近都取得了进步，但总体生存（OS）转移性前列腺癌（PCA）仍然很低。这种更新的申请是继续我们的成果努力开发一种新的微管蛋白抑制剂，该抑制剂可以克服与FDA认可的微管蛋白相关的耐药性抑制剂，因此会增加使用抗微管蛋白药物的PCA和其他类型的癌症的OS。前一期资金的支持导致了新药候选人Veru-1111，这是在第二阶段的转移PCA临床试验下。而Veru-1111正在走上未来FDA的有前途的途径批准，有很大的改进空间。这种续订的目标是：（1）开发下一个 Veru-111的产生以主动解决其预期的耐药性；（2）开发有针对性的veru- 111药物结合物增加了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-1111，可以克服紫杉烷耐药性和预期的VERU-111电阻。初步数据：我们发现了基于Veru-111的混合脚手架和以Ship-216代表的Azixa可以克服对紫杉地和Veru-1111的抵抗。方法：在高分辨率X射线晶体结构的指导下，我们将优化船216脚手架以进一步改进其效力和类似毒品的特性。新的类似物将针对一系列PCA细胞系进行评估，包括在AIM 3中，为体内功效研究选择最佳的五个类似物，可为紫杉烷 - 和VERU-111耐药细胞系选择最佳的五个类似物。 AIM 2。与PSMA靶向部分的共轭Veru-111，以增加PCA的药物积累肿瘤和结合Veru-111与双膦酸盐，可更有效地靶向骨转移。初步数据：我们已经证明了Veru-111本身可以显着减少PDX模型中的骨转移。我们还开发了将Veru-111与PSMA靶向部分或双膦酸盐结合的接头。方法：我们将优化链接器对靶向部分的链接器的长度和组成并使用在结合中，不同的双膦酸盐，以生成一组聚焦的VERU-111药物共轭物。这些结合物将在体外首先评估，以便选择最佳的四个偶联物（其中两个 PMSA和两个在双膦酸盐结合物中）在AIM 3中进行进一步的体内功效研究。 AIM 3。我们将确定最大耐受剂量（MTD），药代动力学（PK）和体内来自PCA细胞系模型中AIMS 1-2所选九种化合物的功效和PDX模型选择总体最佳化合物，以支持VERU-111组合中随后的临床试验。初步数据：我们已经证明，作为新的Veru-111 Analog Ship-216对多种异种移植模型，包括22RV1 PCA和VERU-111抗性DU-145/VXR PCA模型。方法：我们将评估所有选定的新化合物的设计能力治疗前列腺肿瘤在体内使用细胞系和PDX模型。