Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 19, Pages 7900-7915Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501177w
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Funding
- U.S. National Institutes of Health [DK082971-02S1, AR057374-03S1, HL079943, AR057374]
- Pulmonary Hypertension Association
- a Leducq Foundation Transatlantic Network of Excellence Award
- Howard Hughes Medical Institute Early Career Physician-Scientist Award
- Harvard NeuroDiscovery Center
- FOP action UK
- FOP France
- Structural Genomics Consortium
- AbbVie
- Bayer PHARMA AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
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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 ghoma (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-beta 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-beta inhibiton. This 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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