<i>In Vivo</i> Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

Hao, Jijun; Ho, Joshua N.; Lewis, Jana A.; Karim, Kaleh; Daniels, R. Nathan; Gentry, Patrick R.; Hopkins, Corey R.; Lindsley, Craig W.; Hong, Charles C.

doi:10.1021/cb9002865

Cited by 347 publications

(372 citation statements)

References 34 publications

(61 reference statements)

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“…In conclusion, although chemical inhibitors to the BMP type I receptors could be possible medicinal agents for FOP, 5,8 they further affect normal ALK2 receptor 7 and other BMP type I receptors, 9 as well as pathogenic (mutant) ALK2 receptors. Thus, the risk of adverse effects of the inhibitors cannot be excluded at present, and such problems remain to be solved.…”

Section: Resultsmentioning

confidence: 99%

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

et al. 2011

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Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by progressive heterotopic bone formation. Currently, no definitive treatment exists for FOP. The activin receptor type IA / activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the responsible gene for FOP, and disease-associated ALK2 mutations have been found. Chemical inhibitors to the pathogenic ALK2 receptors are considered possible medical agents for FOP, but their adverse effects on normal ALK2 and other receptors cannot be excluded. Here we describe another treatment strategy for FOP using allele-specific RNA interference (ASP-RNAi), and show modified small interfering RNAs (siRNAs) conferring allele-specific silencing against disease-causing ALK2 mutants found in FOP, without affecting normal ALK2 allele. Thus, the siRNAs presented here may become novel therapeutic agents for FOP, and their induced ASP-RNAi may pave the way for the achievement of radical treatment of FOP and/or for the relief of its severe symptoms.

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Section: Resultsmentioning

confidence: 99%

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

et al. 2011

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“…However, the doses are above IC 50 of DM on AMP activated kinase and vascular endothelial growth factor kinase [19], although it is not known whether these kinases have significant roles in T cells. Besides, recombinant Noggin did not have remarkable effects in suppressing proliferation and differentiation (data not shown).…”

Section: Discussionmentioning

confidence: 97%

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

et al. 2011

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Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4 1 T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4 1 T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dosedependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.

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“…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. Therefore, the clinical use of current BMP inhibitors is questionable (24).…”

Section: Introductionmentioning

confidence: 99%

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

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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In Vivo Structure−Activity Relationship Study of Dorsomorphin Analogues Identifies Selective VEGF and BMP Inhibitors

Cited by 347 publications

References 34 publications

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

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

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