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.

项目概要 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% 的肺癌患者将死于骨形态发生蛋白 2 (BMP-)。 2) 属于转化生长因子  (TGF) 超家族的一部分，是一种重要的形态发生素 在 98% 的肺癌中异常过度表达。 BMP 信号级联促进许多癌症的肿瘤发生 BMP 信号调节增殖、 BMP 对癌细胞的迁移、血管生成和存活的调节涉及有效的抗- 我们最近的研究表明，I 型和 II 型 BMP 会抑制凋亡蛋白 XIAP、TAK1 和 Id1。 小分子受体导致胞质和线粒体 Ca2+ 快速持续增加 浓度，这似乎是细胞内 Ca2+ 增加的早期细胞死亡机制。 线粒体通透性 (MMP) 增加、DNA 双链断裂 (DSB) 和细胞死亡。 仅针对 I 型受体的抑制剂不会诱导持续的细胞内 Ca2+ 水平，并且引起的影响要小得多。 细胞死亡后 BMPRII/RI 抑制剂具有持续活性并且是激活所必需的。 I 型受体的 BMPRII 受体还具有介导转录的较长细胞质尾。 独立机制包括调节 XIAP 和 Src，从而增加细胞内 Ca2+ 水平。 BMPRII 将诱导更多的死亡机制，导致 MMP 和 DNA DSB 比 BMPRI 特异性抑制剂 大多数 BMP 抑制剂对 BMPRII 受体的抑制作用很小； 因此，我们预测特定的 BMPRII 抑制剂将比现有的大量抑制剂更有效。 BMP 类似物是从吡唑并[1,5-a]嘧啶核心（PyPy）设计的，其中大部分是 我们使用 X 射线晶体学设计了一种针对 BMPRII 的新型核心分子。 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 此外，我们发现这类新型化合物比肺癌细胞更具有代谢稳定性。 PyPy 类似物。我们现在可以设计有效且特异性的 BMPRII 抑制剂并利用基于细胞的抑制剂。 实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 我们拥有药物化学、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 生物学来优化和研究这些领先的 ​​BMPRII 对于这项拨款提案，我们的目标是 (1) 设计和合成更有效和选择性的 BMPRII。 (2) 评估体外结构活性关系并比较BMPRII BMPRI 抑制剂能够在肺癌细胞系中诱导 BMP 介导的细胞死亡机制。 (3)比较BMPRII和BMPRI探针在小鼠肿瘤异种移植模型中的功效。