Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants

J Med Chem. 2014 Oct 9;57(19):7900-15. doi: 10.1021/jm501177w. Epub 2014 Sep 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 3-(6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenol
  • Aminopyridines
  • Phenols
  • Protein Kinase Inhibitors
  • ACVR1 protein, human
  • Activin Receptors, Type I