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Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2. Here we solved the crystal structure of ALK2 in complex with LDN-212854 to define how its binding interactions compare to previously reported BMP and TGFβ receptor inhibitors. LDN-212854 bound to the kinase hinge region as a typical type I ATP-competitive inhibitor with a single hydrogen bond to ALK2 His286. Specificity arising from the 5-quinoline moiety was associated with a distinct pattern of water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive conformation favoured by ALK2. The structure of this complex provides a template for the design of future ALK2 inhibitors under development for the treatment of FOP and other related conditions of heterotopic ossification.

Original publication

DOI

10.1016/j.bone.2017.09.004

Type

Journal article

Journal

Bone

Publication Date

04/2018

Volume

109

Pages

251 - 258

Keywords

BMP, Crystal structure, Drug, Fibrodysplasia ossificans progressiva, Heterotopic ossification, Kinase inhibitor, Activin Receptors, Type I, Animals, Bone Morphogenetic Protein Receptors, Myositis Ossificans, Protein Binding, Pyrazoles, Pyrimidines, Quinolines, Sf9 Cells