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，尽管医疗保健取得了进步， 85%的肺癌患者会死于这种疾病。骨形态发生蛋白2（BMP-2） 2），其是转化生长因子β（TGF β）超家族的一部分，是一种必需的形态原， 在98%的肺癌中异常过度表达。现在有大量证据表明， BMP信号级联在许多癌中促进肿瘤发生。BMP信号传导调节增殖， 迁移、血管生成和癌细胞存活。BMP对生存的调节涉及到有效的抗- 凋亡蛋白XIAP、TAK 1和Id 1。我们最近的研究表明，抑制BMP I型和II型 受体与小分子引起细胞质和线粒体Ca 2+的快速和持续的增加 浓度，这似乎是一种早期细胞死亡机制。细胞内Ca ~（2+）的增加， 线粒体通透性（MMP）增加，DNA双链断裂（DSB）和细胞死亡。BMP 仅靶向I型受体的抑制剂不诱导持续的细胞内Ca 2+水平， 细胞死亡，然后BMPRII/RI抑制剂。BMPRII受体是组成型活性的，并且是激活 I型受体。BMPRII受体也有一个较长的胞质尾区，介导转录 独立的机制，包括XIAP和Src的调节，增加细胞内Ca 2+水平。我们 假设抑制BMPRII将诱导更多死亡机制，导致MMP增加， DNA DSB比BMPRI特异性抑制剂。大多数BMP抑制剂对BMPRII受体几乎没有抑制作用; 因此，我们预测特定的BMPRII抑制剂将比现有的抑制剂更有效。广大 已经从吡唑并[1，5-a]嘧啶核心（PyPy）设计了100多种BMP类似物，其中大部分是 代谢不稳定我们使用X射线晶体学设计了一种靶向BMPRII的新型核心分子。我们 最先进的新型类似物抑制BMP II型受体，减少BMP信号传导，并诱导死亡， 肺癌细胞。此外，我们表明，这类新的化合物是更代谢稳定比 PyPy类似物。我们现在能够设计有效和特异性的BMPRII抑制剂，并利用基于细胞的 试验和异种移植小鼠模型来检查BMP抑制导致细胞死亡的机制 癌细胞我们在药物化学，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生物学优化和研究这些领先的BMPRII 抑制剂的本研究的目的是：（1）设计和合成更有效和更有选择性的BMPRII 我们的新核心抑制剂。(2)评价体外构效关系并比较BMPRII BMPRI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BMPRII和BMPRI探针在小鼠肿瘤异种移植模型中的功效。