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：
10672554
负责人：
JOHN LANGENFELD
金额：
$ 20.15万
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/10672554
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

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，尽管医疗保健取得了进步， 85% 被诊断患有肺癌的患者将死于这种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，是一种重要的形态发生素，目前有重要证据表明，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，这似乎是一种早期细胞死亡机制。随后线粒体通透性 (MMP) 增加、DNA 双链断裂 (DSB) 和细胞死亡。仅针对 I 型受体的 BMP 抑制剂不会诱导持续的细胞内 Ca2+ 水平并导致细胞死亡比 BMPRII/RI 抑制剂少得多，BMPRII 受体具有持续活性，并且是 BMPRII 受体必需的。 BMPRII 受体还具有介导 I 型受体的激活的较长细胞质尾。转录独立机制，包括 XIAP 和 Src 的调节，这会增加细胞内我们认为抑制 BMPRII 会诱导更多的死亡机制，从而导致死亡。与 BMPRI 特异性抑制剂相比，MMP 和 DNA DSB 增加大多数 BMP 抑制剂几乎没有。抑制 BMPRII 受体；因此我们预测特定的 BMPRII 抑制剂将比大量的 BMP 类似物是从吡唑并[1,5-a]嘧啶核心设计的。（PyPy），其中大多数在代谢上不稳定，我们使用 X 射线晶体学设计了一种新颖的核心。我们最先进的新型类似物靶向 BMPRII 分子，可抑制 BMP II 型受体，降低 BMP 水平。 BMP 信号传导，并诱导肺癌细胞死亡。化合物比 PyPy 类似物代谢更稳定，我们现在可以设计出有效且有效的化合物。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来检查 BMP 抑制导致癌细胞死亡的机制我们拥有医学方面的专业知识。化学、计算生物学、X 射线晶体学、人源化小鼠模型、兽医病理学家和用于优化和研究这些主要 BMPRII 抑制剂的 BMP 生物学对于本拨款提案，我们的目标是 (1) 设计。并从我们的新型核心合成更有效和选择性的 BMPRII 抑制剂 (2) 体外评估。构建活性关系并比较 BMPRII 与 BMPRI 抑制剂诱导 BMP 的能力 (3) BMPRII与BMPRI的疗效比较小鼠肿瘤异种移植模型中的探针。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.

DOI：
10.1038/s41598-022-17446-y
发表时间：
2022-07-30
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Mondal, Arindam;Jia, Dongxuan;Bhatt, Vrushank;Akel, Moumen;Roberge, Jacques;Guo, Jessie Yanxiang;Langenfeld, John
通讯作者：
Langenfeld, John

Bone morphogenetic protein signaling regulation of AMPK and PI3K in lung cancer cells and C. elegans.

DOI：
10.1186/s13578-022-00817-3
发表时间：
2022-05-31
期刊：
CELL AND BIOSCIENCE
影响因子：
7.5
作者：
Vora, Mehul;Mondal, Arindam;Jia, Dongxuan;Gaddipati, Pranya;Akel, Moumen;Gilleran, John;Roberge, Jacques;Rongo, Christopher;Langenfeld, John
通讯作者：
Langenfeld, John

Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.

DOI：
10.1007/s11010-022-04383-7
发表时间：
2022-05
期刊：
Molecular and cellular biochemistry
影响因子：
4.3
作者：
Kaye J;Mondal A;Foty R;Jia D;Langenfeld J
通讯作者：
Langenfeld J

Bone morphogenetic protein receptor 2 inhibition destabilizes microtubules promoting the activation of lysosomes and cell death of lung cancer cells.

DOI：
10.1186/s12964-021-00743-w
发表时间：
2021-09-25
期刊：
Cell communication and signaling : CCS
影响因子：
0
作者：
Mondal A;NeMoyer R;Vora M;Napoli L;Syed Z;Langenfeld E;Jia D;Peng Y;Gilleran J;Roberge J;Rongo C;Jabbour SK;Langenfeld J
通讯作者：
Langenfeld J