Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2

Journal article

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.

Authors: Williams, E; Bullock, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Bone
• Volume: 109
• Pages: 251-258
• Publication date: 2017-09-12
• Acceptance date: 2017-09-11
• DOI: 10.1016/j.bone.2017.09.004
• EISSN: 1873-2763
• ISSN: 8756-3282
• Pmid: 28918311
• Language: English
• Keywords: Kinase inhibitor; Crystal structure; Fibrodysplasia ossificans progressiva; BMP; Heterotopic ossification; Drug