A new class of small molecule inhibitor of BMP signaling.
File(s)
Author(s)
Type
Journal Article
Abstract
Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.
Date Issued
2013-04-30
Date Acceptance
2013-03-24
Citation
PLoS One, 2013, 8 (4), pp.e62721-e62721
ISSN
1932-6203
Publisher
Public Library of Science
Start Page
e62721
End Page
e62721
Journal / Book Title
PLoS One
Volume
8
Issue
4
Copyright Statement
© 2013 Sanvitale et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/23646137
PII: PONE-D-13-00538
Subjects
Activin Receptors, Type I
Aminopyridines
Animals
Body Patterning
Bone Morphogenetic Proteins
Humans
Models, Molecular
Molecular Conformation
Neovascularization, Physiologic
Phenols
Protein Binding
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Signal Transduction
Smad Proteins
Zebrafish
Publication Status
Published online
Coverage Spatial
United States
Article Number
e62721