title: DMH1, a small molecule inhibitor of BMP type i receptors, suppresses growth and invasion of lung cancer.
abstract: The bone morphogenetic protein (BMP) signaling cascade is aberrantly activated in human non-small cell lung cancer (NSCLC) but not in normal lung epithelial cells, suggesting that blocking BMP signaling may be an effective therapeutic approach for lung cancer. Previous studies demonstrated that some BMP antagonists, which bind to extracellular BMP ligands and prevent their association with BMP receptors, dramatically reduced lung tumor growth. However, clinical application of protein-based BMP antagonists is limited by short half-lives, poor intra-tumor delivery as well as resistance caused by potential gain-of-function mutations in the downstream of the BMP pathway. Small molecule BMP inhibitors which target the intracellular BMP cascades would be ideal for anticancer drug development. In a zebrafish embryo-based structure and activity study, we previously identified a group of highly selective small molecule inhibitors specifically antagonizing the intracellular kinase domain of BMP type I receptors. In the present study, we demonstrated that DMH1, one of such inhibitors, potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in NSCLC cells by blocking BMP signaling, as indicated by suppression of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3. Additionally, DMH1 treatment significantly reduced the tumor growth in human lung cancer xenograft model. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel strategy for lung cancer treatment.
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Andy
authors.initials: A
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Fan
authors.affiliation: College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Chantelle
authors.initials: C
authors.lastname: Labib
authors.affiliation: Department of Clinical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Parsa
authors.affiliation: Department of Clinical Sciences, College of Osteopathic Medicine, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Orlando
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Bradley
authors.initials: B
authors.lastname: Andresen
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C583032:DMH1 compound; D011720:Pyrazoles; D011804:Quinolines; D052005:Bone Morphogenetic Protein Receptors, Type I