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

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 b...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2014-10, Vol.57 (19), p.7900-7915
Main Authors: Mohedas, Agustin H, Wang, You, Sanvitale, Caroline E, Canning, Peter, Choi, Sungwoon, Xing, Xuechao, Bullock, Alex N, Cuny, Gregory D, Yu, Paul B
Format: Article
Language:English
Subjects:
Activin Receptors, Type I - antagonists & inhibitors
Activin Receptors, Type I - genetics
Aminopyridines - chemical synthesis
Aminopyridines - metabolism
Aminopyridines - pharmacology
Humans
Mutation
Myositis Ossificans - drug therapy
Myositis Ossificans - genetics
Phenols - pharmacology
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501177w