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Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants

DOI: 10.1021/jm501177w DOI Help
PMID: 25101911 PMID Help

Authors: Agustin H. Mohedas (Harvard−MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology) , You Wang (Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital and Harvard Medical School) , Caroline E. Sanvitale (Structural Genomics Consortium, University of Oxford) , Peter Canning (Structural Genomics Consortium, University of Oxford) , Sungwoon Choi (Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital and Harvard Medical School) , Xuechao Xing (Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital and Harvard Medical School) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford) , Gregory D. Cuny (Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women’s Hospital and Harvard Medical School) , Paul B. Yu (Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 57 (19) , PAGES 7900 - 7915

State: Published (Approved)
Published: October 2014

Open Access Open Access

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.

Journal Keywords: Type; Aminopyridines; Humans; Mutation; Myositis; Phenols; Protein; Structure-Activity RelationshipHoward Hughes Medical Institute Early Career Physician-Scientist Award; FOP action UK; FOP France; Structural Genomics Consortium

Subject Areas: Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)