title: A new class of small molecule inhibitor of BMP signaling.
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.
authors: Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
authors: Caroline E
authors: CE
authors: Sanvitale
authors: Georgina
authors: G
authors: Kerr
authors: Apirat
authors: A
authors: Chaikuad
authors: Marie-Christine
authors: MC
authors: Ramel
authors: Agustin H
authors: AH
authors: Mohedas
authors: Sabine
authors: S
authors: Reichert
authors: You
authors: Y
authors: Wang
authors: James T
authors: JT
authors: Triffitt
authors: Gregory D
authors: GD
authors: Cuny
authors: Paul B
authors: PB
authors: Yu
authors: Caroline S
authors: CS
authors: Hill
authors: Alex N
authors: AN
authors: Bullock
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000737:chemistry; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D015027:Zebrafish
chemical_list: C584410:3-(6-amino-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenol; D000631:Aminopyridines; D019485:Bone Morphogenetic Proteins; C554430:LDN 193189; D010636:Phenols; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C032439:alpha-aminopyridine
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