Mohedas, Agustin H.Wang, YouSanvitale, Caroline E.Canning, PeterChoi, SungwoonXing, XuechaoBullock, Alex N.Cuny, Gregory D.Yu, Paul2015-09-012014Mohedas, Agustin H., You Wang, Caroline E. Sanvitale, Peter Canning, Sungwoon Choi, Xuechao Xing, Alex N. Bullock, Gregory D. Cuny, and Paul B. Yu. 2014. “Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants.” Journal of Medicinal Chemistry 57 (19): 7900-7915. doi:10.1021/jm501177w. http://dx.doi.org/10.1021/jm501177w.0022-2623http://nrs.harvard.edu/urn-3:HUL.InstRepos:21462457There 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.en-USArticleJournal Article2015-09-0110.1021/jm501177w