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.

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

“…We also used a small-molecule inhibitor of BMP signaling, DMH1, to block pathway activity. DMH1 can suppress the growth of BMP-dependent ovarian and lung cancer cells (36,37), but its efficacy in melanoma has not been reported. DMH1 inhibits the kinase activity of ALK2 and BMPR1A (ALK3) receptors but not of BMPR1B (ALK6), thereby abrogating phosphorylation and activation of the SMAD1/5/8 transcriptional cascade (38).…”

Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer

“…Dorsomorphin was identified as a potent BMP inhibitor, and its analogue, DMH-1, Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001, as determined by Student t test (A and C, bottom) or two-way ANOVA (C, top). disturbs lung cancer growth and breast cancer metastasis (38,39). LDN-193189 was reported to inhibit growth of breast and prostate cancers in vivo and prolong survival of mice bearing ovarian cancer cells (40)(41)(42).…”

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

“…Therefore, C4-like antibodies have an important potential for clinical, diagnostic, and therapeutic uses in a subset of colorectal cancers. As BMP4 has also been shown to contribute to carcinogenesis in breast (12), lung (14), prostate (15), and gastric (18) cancers, the oncologic applicability of C4-like antibodies is considerable.…”

“…Most intriguing is the role of BMP4, which presents opposing roles depending on the neoplasm (7,9). In certain malignancies, such as glioblastoma (10) and myeloma (11), high levels of BMP4 are associated with less malignant features while in breast (12), ovarian (13), lung (14), and prostate (15), BMP4 is involved in epithelial-mesenchymal transition (EMT) and metastatic behavior. In gastrointestinal cancers such as pancreas (16), colon (17), and gastric cancer (18), BMP4 has been associated with tumor progression and chemotherapy resistance.…”

“…Neutralization of BMP by several natural antagonists and chemical inhibitors has already been proven successful for the suppression of metastasis in prostate (15), lung (14), as well as breast cancer (20). Albeit significant progress has been made in generating highly specific and less toxic small-molecule inhibitors that target BMP type I receptors (21)(22)(23), these inhibitors are still nonselective.…”