Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1371/journal.pone.0062721

Type

Journal article

Journal

PloS one

Publication Date

01/2013

Volume

8

Addresses

Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.

Keywords

Animals, Zebrafish, Humans, Aminopyridines, Phenols, Pyrazoles, Pyrimidines, Activin Receptors, Type I, Bone Morphogenetic Proteins, Protein Kinase Inhibitors, Signal Transduction, Molecular Conformation, Protein Binding, Body Patterning, Neovascularization, Physiologic, Models, Molecular, Smad Proteins