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Updated: Feb 7, 2026

Site-Directed Immobilization of Bone Morphogenetic Protein 2 to Solid Surfaces by Click Chemistry
Published on: March 29, 2018
Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1
Lara S Kallander1, David Washburn1, Mark A Hilfiker1
1Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, and Platform Technology and Sciences, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, United States.
Abstract:
Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.
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