title: Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants.
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.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
authors.forename: Agustin H
authors.initials: AH
authors.lastname: Mohedas
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sanvitale
authors.forename: Peter
authors.initials: P
authors.lastname: Canning
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Choi
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics; D000631:Aminopyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D009221:Myositis Ossificans / Q000188:drug therapy* / Q000235:genetics; D010636:Phenols / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C584410:3-(6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenol; D000631:Aminopyridines; D010636:Phenols; D047428:Protein Kinase Inhibitors; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
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