Developing bone morphogenetic receptor II inhibitors for the treatment of cancer

开发用于治疗癌症的骨形态发生受体 II 抑制剂

基本信息

批准号：
10405106
负责人：
JOHN LANGENFELD
金额：
$ 35.64万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405106
关键词：
Apoptotic Applications Grants BIRC4 gene BMP2 gene BMPR2 gene Binding Proteins Biological Assay Biology Bone Morphogenetic Proteins Cancer Etiology Cancer Patient Cancer cell line Carcinoma Caring Cell Death Cell Survival Cells Cessation of life Complement Factor B Computational Biology Crystallization Crystallography Cytoplasmic Tail DNA Double Strand Break Diagnosis Digit structure Disease Down-Regulation Drug Kinetics Embryo Genetic Transcription Goals Half-Life In Vitro Lead Liver Microsomes Luciferases Lung MAP3K7 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Metabolic Mitochondria Modeling Mus Operative Surgical Procedures Pathologist Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Plasma Plasma Proteins Positioning Attribute Property Protein Inhibition Proteins Publishing Pyrimidine Regulation Reporting Research Resected Signaling Protein Site Specificity Structure Structure of parenchyma of lung Structure-Activity Relationship Toxic effect Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transforming Growth Factors United States Veterinarians Western Blotting X-Ray Crystallography Xenograft Model Xenograft procedure analog angiogenesis anti-cancer base bone bone morphogenetic protein receptor type I bone morphogenetic protein receptors cancer cell cancer survival cancer therapy cancer type comparative efficacy constitutive active receptor design humanized mouse in vivo inhibitor lead optimization lung Carcinoma lung cancer cell migration morphogens mouse model novel overexpression promoter pyridine receptor small molecule success tumor tumor growth tumor progression tumor xenograft tumorigenesis

Apoptotic Applications Grants BIRC4 gene BMP2 gene BMPR2 gene Binding Proteins Biological Assay Biology Bone Morphogenetic Proteins Cancer Etiology Cancer Patient Cancer cell line Carcinoma Caring Cell Death Cell Survival Cells Cessation of life Complement Factor B Computational Biology Crystallization Crystallography Cytoplasmic Tail DNA Double Strand Break Diagnosis Digit structure Disease Down-Regulation Drug Kinetics Embryo Genetic Transcription Goals Half-Life In Vitro Lead Liver Microsomes Luciferases Lung MAP3K7 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Metabolic Mitochondria Modeling Mus Operative Surgical Procedures Pathologist Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Plasma Plasma Proteins Positioning Attribute Property Protein Inhibition Proteins Publishing Pyrimidine Regulation Reporting Research Resected Signaling Protein Site Specificity Structure Structure of parenchyma of lung Structure-Activity Relationship Toxic effect Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transforming Growth Factors United States Veterinarians Western Blotting X-Ray Crystallography Xenograft Model Xenograft procedure analog angiogenesis anti-cancer base bone bone morphogenetic protein receptor type I bone morphogenetic protein receptors cancer cell cancer survival cancer therapy cancer type comparative efficacy constitutive active receptor design humanized mouse in vivo inhibitor lead optimization lung Carcinoma lung cancer cell migration morphogens mouse model novel overexpression promoter pyridine receptor small molecule success tumor tumor growth tumor progression tumor xenograft tumorigenesis

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项目摘要

Lung cancer is the leading cause of cancer deaths in the United States and despite advances in medical care, 85% of patients diagnosed with lung cancer will die from the disease. The bone morphogenetic protein 2 (BMP-2), which is part of the transforming growth factor β (TGFβ) superfamily, is an essential morphogen that is aberrantly over-expressed in 98% of lung cancers. There is now significant evidence demonstrating that the BMP signaling cascade promotes tumorigenesis in many carcinomas. BMP signaling regulates proliferation, migration, angiogenesis, and survival of cancer cells. BMP regulation of survival involves the potent anti- apoptotic proteins XIAP, TAK1, and Id1. Our recent studies show that suppression of BMP type I and type II receptors with small molecules causes a rapid and sustained increase in cytosolic and mitochondrial Ca2+ concentrations, which appears to be an early cell death mechanism. The increase in intracellular Ca2+ is followed by an increase in mitochondrial permeability (MMP), DNA double strand breaks (DSB), and cell death. BMP inhibitors that only target the type I receptors do not induce sustained intracellular Ca2+ levels and cause far less cell death then BMPRII/RI inhibitors. BMPRII receptors are constitutively active and are required for the activation of type I receptors. The BMPRII receptor also has a longer cytoplasmic tail that mediates transcription independent mechanisms including the regulation of XIAP and Src, which increases intracellular Ca2+ levels. We hypothesize that inhibition of BMPRII will induce more death mechanisms leading to an increase in MMP and DNA DSB than BMPRI specific inhibitors. The majority of BMP inhibitors have little inhibition of BMPRII receptors; therefore we predict a specific BMPRII inhibitor would be more potent than existing inhibitors. The vast number of BMP analogs has been designed from pyrazolo [1,5-a] pyrimidine core (PyPy), the majority of which are metabolically unstable. We used X-ray crystallography to design a novel core molecule that targets BMPRII. Our most advanced novel analog inhibits the BMP type II receptor, decreases BMP signaling, and induces death of lung cancer cells. Furthermore, we show that this novel class of compounds is more metabolically stable than PyPy analogs. We are now in position to design potent and specific BMPRII inhibitors and utilize cell based assays and xenograft mouse models to examine the mechanisms by which BMP inhibition leads to cell death of cancer cells. We have the expertise in medicinal chemistry, computational biology, X-ray crystallography, humanized mice models, veterinarian pathologist, and BMP biology to optimize and study these lead BMPRII inhibitors. For this grant proposal, we aim to (1) Design and synthesize more potent and selective BMPRII inhibitors from our novel core. (2) Evaluate in vitro structure activity relationships and compare BMPRII to BMPRI inhibitors in their ability induce BMP mediated cell death mechanisms in lung cancer cell lines. (3) Compare efficacy of BMPRII and BMPRI probes in mouse tumor xenograft models.

肺癌是美国癌症死亡的主要原因，目的地在医疗保健方面的进步， 85％的被诊断为肺癌的患者将死于该疾病。骨形态发生蛋白2 （BMP-2）是转化生长因子β（TGFβ）超家族的一部分，是必不可少的形态学在98％的肺癌中，异常过表达。现在有大量证据表明 BMP信号级联反应促进许多癌中的肿瘤发生。 BMP信号传导调节增殖，癌细胞的迁移，血管生成和存活。 BMP的生存调节涉及潜在的抗凋亡蛋白XIAP，TAK1和ID1。我们最近的研究表明，抑制BMP I型和II型具有小分子的受体会导致胞质和线粒体Ca2+的快速持续增加浓度似乎是一种早期的细胞死亡机制。细胞内Ca2+的增加为然后增加线粒体通透性（MMP），DNA双链断裂（DSB）和细胞死亡。仅针对I型受体的BMP抑制剂不会诱导持续的细胞内Ca2+水平 BMPRII/RI抑制剂少得多。 BMPRII受体始终保持活跃，需要 I型受体的激活。 BMPRII受体还具有较长的细胞质尾巴转录独立的机制，包括XIAP和SRC的调节，这会增加细胞内 Ca2+水平。我们假设抑制BMPRII将引起更多的死亡机制与BMPRI特异性抑制剂相比，MMP和DNA DSB的增加。大多数BMP抑制剂几乎没有 BMPRII受体的抑制；因此，我们预测特定的BMPRII抑制剂将比现有的抑制剂。大量BMP类似物是由吡唑洛[1,5-A]嘧啶核设计的（pypy），大多数是代谢不稳定的。我们使用X射线晶体学设计了一种新型核心靶向BMPRII的分子。我们最先进的小说模拟抑制了BMP II型受体，下降 BMP信号传导，并诱导肺癌细胞死亡。此外，我们证明了这个小说的班级化合物在代谢上比PYPY类似物更稳定。我们现在可以设计潜力，特定的BMPRII抑制剂并利用基于细胞的测定和异种移植小鼠模型检查 BMP抑制导致癌细胞的细胞死亡的机制。我们有医疗方面的专业知识化学，计算生物学，X射线晶体学，人源化小鼠模型，兽医病理学家和 BMP生物学以优化和研究这些铅BMPRII抑制剂。对于此赠款提案，我们的目标是（1）设计并从我们的新核心中综合了更多的潜力和选择性BMPRII抑制剂。（2）评估体外结构活动关系并将BMPRII与BMPRI抑制剂进行比较，以诱导BMP 肺癌细胞系中介导的细胞死亡机制。（3）比较BMPRII和BMPRI的效率小鼠肿瘤特征模型中的问题。