Exploration of a Mutant p53 Reactivating Compound

突变型 p53 重新激活化合物的探索

• 批准号: 9315121
• 负责人: Darren Richard Carpizo
• 金额: $ 15.9万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-16 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315121
• 关键词: Acetylcysteine; Address; Affinity; Alleles; Antineoplastic Agents; Apoptosis; Apoptotic; Area; Binding; Binding Proteins; Biophysics; Buffers; California; Cancer Institute of New Jersey; Cancer Model; Cellular biology; Chelating Agents; Chemistry; Clinic; Clinical Trials; Comprehensive Cancer Center; Computer Simulation; Copper; DNA Binding Domain; Data; Development; Development Plans; Developmental Therapeutics Program; Diamide; Discipline; Doctor of Philosophy; Dose; Drug Kinetics; Drug Targeting; Educational workshop; Enrollment; Environment; Erinaceidae; Family; Funding; Future; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; Impairment; Instruction; International; Ions; Iron; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Los Angeles; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metals; Methodology; Modeling; Molecular; Molecular Biology; Mus; Mutate; Mutation; Normal Cell; Olives - dietary; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxides; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pilot Projects; Post-Translational Protein Processing; Principal Investigator; Property; Protein p53; Proteins; RNA Interference; Reducing Agents; Research; Research Design; Research Project Grants; Research Support; Resectable; Residencies; Running; Scientist; Source; Structural Biologist; Structure; Surgical Oncologist; Surgical Oncology; TP53 gene; Techniques; Technology; Testing; Therapeutic; Thiosemicarbazones; Training; Transgenic Mice; Tumor Suppressor Proteins; United States; United States National Institutes of Health; Universities; Zinc; anti-cancer therapeutic; cancer cell; career; career development; chelation; clinical development; design; drug development; efficacy study; experience; experimental study; hepatobiliary cancer; in vivo; inhibitor/antagonist; killings; mouse model; mutant; novel; preclinical development; preclinical study; professor; programs; protein folding; public health relevance; restoration; screening; translational clinical trial; tumor growth; tumor xenograft; zinc-binding protein; Acetylcysteine; Address; Affinity; Alleles; Antineoplastic Agents; Apoptosis; Apoptotic; Area; Binding; Binding Proteins; Biophysics; Buffers; California; Cancer Institute of New Jersey; Cancer Model; Cellular biology; Chelating Agents; Chemistry; Clinic; Clinical Trials; Comprehensive Cancer Center; Computer Simulation; Copper; DNA Binding Domain; Data; Development; Development Plans; Developmental Therapeutics Program; Diamide; Discipline; Doctor of Philosophy; Dose; Drug Kinetics; Drug Targeting; Educational workshop; Enrollment; Environment; Erinaceidae; Family; Funding; Future; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Human; Impairment; Instruction; International; Ions; Iron; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Los Angeles; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metals; Methodology; Modeling; Molecular; Molecular Biology; Mus; Mutate; Mutation; Normal Cell; Olives - dietary; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxides; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pilot Projects; Post-Translational Protein Processing; Principal Investigator; Property; Protein p53; Proteins; RNA Interference; Reducing Agents; Research; Research Design; Research Project Grants; Research Support; Resectable; Residencies; Running; Scientist; Source; Structural Biologist; Structure; Surgical Oncologist; Surgical Oncology; TP53 gene; Techniques; Technology; Testing; Therapeutic; Thiosemicarbazones; Training; Transgenic Mice; Tumor Suppressor Proteins; United States; United States National Institutes of Health; Universities; Zinc; anti-cancer therapeutic; cancer cell; career; career development; chelation; clinical development; design; drug development; efficacy study; experience; experimental study; hepatobiliary cancer; in vivo; inhibitor/antagonist; killings; mouse model; mutant; novel; preclinical development; preclinical study; professor; programs; protein folding; public health relevance; restoration; screening; translational clinical trial; tumor growth; tumor xenograft; zinc-binding protein

DESCRIPTION (provided by applicant): TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. We identified NSC319726 (726) as a mutant p53 reactivating compound, and a lead compound for mutant p53 targeted drug development [1]. Prior evidence indicated that the effects of 726 were allele-specific, by restoring wildtype structure and function to the third most common p53 mis-sense mutant (p53-R175H). This effect was dependent on the zinc-chelating and redox modulating properties of 726. The p53 protein binds a single zinc ion, which is necessary for proper p53 structure and function. The p53-R175H mutation impairs the protein from binding zinc causing it to mis-fold and lose transcriptional function. The mechanism of 726 mutant p53 reactivation is unknown. We provide preliminary data that describe a novel "dual" mechanism where 726 restores wild-type structure to the p53-R175H using a zinc-metallochaperone function to provide an optimal concentration of zinc to facilitate proper folding. We also demonstrate that the redox modulating properties of 726 function to transactivate the newly conformed p53-R175 and induce an apoptotic program. We also demonstrate that this zinc-metallochaperone function applies to other p53 mis-sense mutants with impaired zinc binding. In this K08 Career Development Award, Dr Darren Carpizo and his collaborators plan to explore this compound in two major directions. Aim #1 is to dissect the molecular mechanism by which the compound reactivates the p53-R175 mutant protein and other p53 zinc-binding mutants. Aim #2 is conduct pre-clinical studies of the compound to evaluate its potential for clinical development as a mutant p53 targeted anti-cancer drug. Dr. Carpizo is a surgical oncologist specializing in hepatobiliary and pancreatic cancers currently appointed as an assistant professor of surgery at The Cancer Institute of New Jersey (CINJ), an NCI designated Comprehensive Cancer Center. He has obtained formalized training in research at the University of California at Los Angeles, earning a PhD in molecular and cell biology during his general surgical residency training. Dr. Arnold Levine whose laboratory discovered the p53 tumor suppressor and Dr. Joseph Bertino, an internationally recognized expert in the field of Developmental Therapeutics in cancer, are currently mentoring him. Dr. Carpizo's immediate and long term career goals are to 1) Build an independent NIH Research Project Grant supported research program focusing on pancreatic cancer, 2) Become a leader of a dedicated group of clinicians and scientists that focus on pancreatic cancer at an NCI designated Comprehensive Cancer Center and 3) To develop a niche of Developmental Therapeutics within the broader discipline of Surgical Oncology. The Career Development Plan designed by Dr. Carpizo and his Mentor/Co-Mentor will accomplish these goals with three major components: 1) Laboratory research: The candidate will execute the research plan outlined above under the mentorship of Drs. Levine and Bertino. He will receive further instruction from several collaborators including Dr. Stewart Loh, a biochemist who will conduct biophysical experiments with NSC319726. Dr. Gaetano Montelione, an NMR structural biologist who will attempt to use NMR techniques to study drug-p53-R175 protein interactions and Dr. Ken Olive, a molecular biologist who runs a NIH funded pancreatic cancer laboratory with expertise in the transgenic mouse model of pancreas cancer that will be used to test NSC319726. Dr. Carpizo will also receive specialized instruction in using RNAi technologies in mouse cancer modeling from Dr. Scott Lowe, (Memorial Sloan-Kettering cancer center). 2) Experience in Translational Clinical Trials: Dr. Carpizo will gain experience in translational clinical trials through the conduct of small pilot study designed to study the mechanism of action of the Novartis Hedgehog inhibitor (LDE-225) in patients with surgically resectable pancreas cancer. Dr. Carpizo is the principal investigator of this clinical trial that is being funded by Novartis. Dr. Bertino will mentor him through the conduct of this trial. 3) Didactics: Dr. Carpizo will take attend several courses at Cold Spring Harbor including 1) Advanced Sequencing Technologies, and 2) Mechanisms and Models of Cancer and 3) Workshop on Pancreatic Cancer.

描述（由申请人提供）：TP53是人类癌症中最常见的突变基因，不存在有效的靶向抗癌药物。我们将NSC319726（726）确定为突变p53重新激活化合物，而突变体p53靶向药物发育的铅化合物[1]。先前的证据表明，通过将野生型结构和功能恢复到第三个常见的p53错误 - 宽敞突变体（p53-r175h），726的作用是等位基因特异性的。这种作用取决于726的锌授予和氧化还原调节性能。p53蛋白结合了单个锌离子，这对于适当的p53结构和功能是必不可少的。 p53-R175H突变会损害蛋白质结合锌，从而导致其折叠并失去转录功能。 726突变体P53重新激活的机制尚不清楚。我们提供了描述一种新颖的“双重”机制的初步数据，其中726使用锌 - 金呼吸器函数恢复p53-R175H的野生型结构，以提供最佳的锌浓度以促进适当的折叠。我们还证明了726功能的氧化还原调节特性以反式激活新构象的p53-R175并诱导凋亡程序。我们还证明，该锌 - 金呼吸蛋白功能适用于具有锌结合受损的其他p53失误突变体。在这个K08职业发展奖中，Darren Carpizo博士和他的合作者计划在两个主要方向上探索这种化合物。目的＃1是剖析化合物将p53-R175突变蛋白和其他p53锌结合突变体重新激活的分子机制。 AIM＃2是对化合物进行临床前研究，以评估其作为突变体p53靶向抗癌药物的临床发育潜力。 Carpizo博士是一名外科肿瘤学家，专门从事肝素和胰腺癌目前被任命为新泽西州癌症研究所（CINJ）的助理教授，NCI指定综合癌症中心。他在加利福尼亚大学洛杉矶分校获得了正式的研究培训，在他的一般手术居住培训期间获得了分子和细胞生物学博士学位。阿诺德·莱文（Arnold Levine）博士的实验室发现p53肿瘤抑制剂和癌症发育疗法领域的国际认可专家约瑟夫·贝蒂诺（Joseph Bertino）目前正在指导他。 Carpizo博士的直接和长期职业目标是1）建立一个独立的NIH研究项目资助支持的研究计划，专注于胰腺癌，2）成为专门的临床医生和科学家组的领导者，该研究专注于NCI的胰腺癌，并指定了综合性癌症中心的NCI癌症和3）在Surgipline of Surgipline of Surgipline of Surgipline of Surglip incipline incipline of surgcipline of cong cong conc inc concline of congic incipline incipline incipline incipline consecipline。 Carpizo博士及其导师/同事设计的职业发展计划将通过三个主要组成部分来实现这些目标：1）实验室研究：候选人将在Drs的指导下执行上述研究计划。莱文和贝蒂诺。他将收到几位合作者的进一步指导，包括生物化学家Stewart Loh博士，他将使用NSC319726进行生物物理实验。 NMR结构生物学家Gaetano Montelione博士将尝试使用NMR技术来研究药物P53-R175蛋白质相互作用，而分子生物学家Ken Olive博士则经营NIH资助的胰腺癌实验室，具有在胰腺癌的转基因小鼠模型中用于测试NSC nsc nsc nsc 36的胰小鼠模型中的专业知识。 Carpizo博士还将从Scott Lowe博士（纪念Sloan-Kettering Cancer Center）中使用RNAi Technologies进行小鼠癌建模中的专门指导。 2）翻译临床试验的经验：Carpizo博士通过进行小型试点研究的经验，旨在研究诺华刺猬抑制剂（LDE-225）的作用机理（LDE-225）对手术可切除的胰腺癌。 Carpizo博士是该临床试验的主要研究者，该试验由诺华资助。伯蒂诺博士将通过这次审判进行指导他。 3）教学学：Carpizo博士将在冷泉港参加几门课程，包括1）高级测序技术，以及2）癌症的机制和模型和3））关于胰腺癌的研讨会。