6BTN

BMP1 complexed with a reverse hydroxymate - compound 1

Summary for 6BTN

• Entry DOI: 10.2210/pdb6btn/pdb
• Descriptor: Bone morphogenetic protein 1, 1,2-ETHANEDIOL, ZINC ION, ... (5 entities in total)
• Functional Keywords: endopeptidase, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 46654.36

Authors

Gampe, R.,Shewchuk, L. (deposition date: 2017-12-07, release date: 2018-08-08, Last modification date: 2024-11-13)

Primary citation

Kallander, L.S.,Washburn, D.,Hilfiker, M.A.,Eidam, H.S.,Lawhorn, B.G.,Prendergast, J.,Fox, R.,Dowdell, S.,Manns, S.,Hoang, T.,Zhao, S.,Ye, G.,Hammond, M.,Holt, D.A.,Roethke, T.,Hong, X.,Reid, R.A.,Gampe, R.,Zhang, H.,Diaz, E.,Rendina, A.R.,Quinn, A.M.,Willette, B.
Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.
ACS Med Chem Lett, 9:736-740, 2018

PubMed 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 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.

PubMed: 30034610
DOI: 10.1021/acsmedchemlett.8b00173

Experimental method

X-RAY DIFFRACTION (2.05 Å)