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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，尽管医疗保健有所进步，

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.

肺癌细胞和秀丽隐杆线虫中AMPK和PI3K的骨形态发生蛋白信号传导调节。

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.

骨形态发生蛋白受体2抑制不稳定的微管，促进溶酶体的激活和肺癌细胞的细胞死亡。

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