ArticleJournal of medicinal chemistry2014
Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 96 citations in OpenAlex.
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- Meta-analysis of functional genomics studies reveals conserved cellular pathways required by viruses of pandemic concern.Access microbiology · 2026Article
- Frequency-Regulated Repeated Micro-Vibration Promotes Osteoblast Differentiation Through BMP Signaling in MC3T3-E1 Cells.Life (Basel, Switzerland) · 2025Article
- Current advances on RIPK2 and its inhibitors in pathological processes: a comprehensive review.Frontiers in molecular neuroscience · 2025Review
- Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer.Cancer research · 2024Article
- ACVR1/ALK2-p21 signaling axis modulates proliferation of the venous endothelium in the retinal vasculature.Angiogenesis · 2024Article
- Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2.Journal of medicinal chemistry · 2024Article
- BMP-ACVR1 Axis is Critical for Efficacy of PRC2 Inhibitors in B-Cell Lymphoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway.ACS pharmacology & translational science · 2023Review
- Identification of an ALK-2 inhibitor as an agonist for intercellular exchange and tumor delivery of nanomaterial.Advanced therapeutics · 2023Article
- RIPK2: a promising target for cancer treatment.Frontiers in pharmacology · 2023Review
- Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification.International journal of molecular sciences · 2022Review
- Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials.Journal of personalized medicine · 2022Review
- Repurposing Vandetanib plus Everolimus for the Treatment ofCancer discovery · 2022Article
- Review
- Tumor cells generate astrocyte-like cells that contribute to SHH-driven medulloblastoma relapse.The Journal of experimental medicine · 2021Article
- Recent Advances in ALK2 Inhibitors.ACS omega · 2021Review
- Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva.JCI insight · 2021Article
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Authors and funding
9 authors at 6 institutions in 2 countries.
Funding
Abstract
There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.