4BGG

Crystal structure of the ACVR1 kinase in complex with LDN-213844

Summary for 4BGG

• Entry DOI: 10.2210/pdb4bgg/pdb
• Descriptor: ACTIVIN RECEPTOR TYPE-1, 1-{4-[5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenyl}piperazine, CITRATE ANION, ... (5 entities in total)
• Functional Keywords: transferase, inhibitor, bmp signalling
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: Q04771
• Total number of polymer chains: 4
• Total formula weight: 141158.26

Authors

Sanvitale, C.,Canning, P.,Cooper, C.,Wang, Y.,Mohedas, A.H.,Choi, S.,Yu, P.B.,Cuny, G.D.,Nowak, R.,Coutandin, D.,Vollmar, M.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.,Structural Genomics Consortium (SGC) (deposition date: 2013-03-26, release date: 2013-04-10, Last modification date: 2024-10-23)

Primary citation

Mohedas, A.H.,Wang, Y.,Sanvitale, C.E.,Canning, P.,Choi, S.,Xing, X.,Bullock, A.N.,Cuny, G.D.,Yu, P.B.
Structure-Activity Relationship of 3,5-Diaryl-2-Aminopyridine Alk2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants.
J.Med.Chem., 57:7900-, 2014

PubMed 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.

PubMed: 25101911
DOI: 10.1021/JM501177W

Experimental method

X-RAY DIFFRACTION (2.56 Å)