Targeting BMP type 2 receptor for the treatment of breast cancer.

靶向 BMP 2 型受体治疗乳腺癌。

• 批准号: 10515890
• 负责人: JOHN LANGENFELD
• 金额: $ 6.32万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515890
• 关键词: Apoptotic; Applications Grants; BIRC4 gene; BMP2 gene; BMPR2 gene; Biological Assay; Biology; Bone Morphogenetic Proteins; Breast Cancer Treatment; Cancer Etiology; Cancer Patient; Cancer cell line; Carcinoma; Caring; Cell Death; Cells; Cessation of life; Computational Biology; Cytoplasmic Tail; DNA Double Strand Break; Diagnosis; Disease; Down-Regulation; Genetic Transcription; In Vitro; Lead; MAP3K7 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medical; Metabolic; Mitochondria; Mus; Pathologist; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Protein Inhibition; Proteins; Pyrimidine; Regulation; Signaling Protein; Structure of parenchyma of lung; Structure-Activity Relationship; Transforming Growth Factors; United States; Veterinarians; X-Ray Crystallography; Xenograft Model; Xenograft procedure; analog; angiogenesis; anti-cancer; base; bone morphogenetic protein receptors; cancer cell; cancer survival; comparative efficacy; constitutive active receptor; design; humanized mouse; inhibitor; lung Carcinoma; lung cancer cell; migration; morphogens; mouse model; novel; overexpression; receptor; small molecule; tumor progression; tumor xenograft; tumorigenesis

PROJECT SUMMARY 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  (TGF) 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.

项目摘要 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（TGF）超家族的一部分，是一种必不可少的形态学 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。遵循细胞内Ca2+的增加 通过增加线粒体通透性（MMP），DNA双链断裂（DSB）和细胞死亡。 BMP 仅针对I型受体的抑制剂不会诱导持续的细胞内Ca2+水平，并且导致较少 细胞死亡然后BMPRII/RI抑制剂。 BMPRII受体始终如一，激活需要 I型受体。 BMPRII受体还具有较长的细胞质尾巴，可介导转录 独立机制，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，从而导致MMP和 DNA DSB比BMPRI特异性抑制剂。大多数BMP抑制剂对BMPRII受体的抑制作用很少。 因此，我们预测特定的BMPRII抑制剂将比现有抑制剂更有潜力。大量 BMP类似物的设计是由吡唑洛斯[1,5-A]嘧啶核（PYPY）设计的，其中大多数是 代谢不稳定。我们使用X射线晶体学来设计靶向BMPRII的新型核心分子。我们的 最先进的新型模拟抑制了BMP II型受体，降低BMP信号，并诱导死亡 肺癌细胞。此外，我们表明，这种新颖的化合物比代谢稳定 PYPY类似物。我们现在可以设计潜在和特定的BMPRII抑制剂并利用基于细胞的抑制剂 测定和异种移植小鼠模型，以检查BMP抑制导致细胞死亡的机制 癌细胞。我们拥有医学化学，计算生物学，X射线晶体学方面的专业知识， 人性化小鼠模型，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）设计和综合更多潜力和选择性的BMPRII 我们新颖核心的抑制剂。 （2）评估体外结构活动关系并比较BMPRII BMPI抑制剂在肺癌细胞系中诱导BMP介导的细胞死亡机制的能力。 （3）比较小鼠肿瘤特征模型中BMPRII和BMPRI问题的效率。