3MTF: Crystal Structure Of The Acvr1 Kinase In Complex With A 2- Aminopyridine Inhibitor

Citation:
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-beta 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.
PDB ID: 3MTFDownload
MMDB ID: 82969
PDB Deposition Date: 2010/4/30
Updated in MMDB: 2014/06
Experimental Method:
x-ray diffraction
Resolution: 2.15  Å
Source Organism:
Similar Structures:
Biological Unit for 3MTF: monomeric; determined by author
Molecular Components in 3MTF
Label Count Molecule
Protein (1 molecule)
1
Activin Receptor Type-1(Gene symbol: ACVR1)
Molecule annotation
Chemicals (16 molecules)
1
4
2
11
3
1
* Click molecule labels to explore molecular sequence information.

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