Summary for 9FRV
| Entry DOI | 10.2210/pdb9frv/pdb |
| Descriptor | Arginase-2, mitochondrial, MANGANESE (II) ION, [(4~{S},5~{S})-4-(aminomethyl)-5-azanyl-6-oxidanyl-6-oxidanylidene-hexyl]-$l^{3}-oxidanyl-bis(oxidanyl)boron, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 110510.77 |
| Authors | Petersen, j. (deposition date: 2024-06-19, release date: 2024-11-27, Last modification date: 2024-12-25) |
| Primary citation | Shields, J.D.,Aquila, B.M.,Emmons, D.,Finlay, M.R.V.,Gangl, E.T.,Gu, C.,Mlynarski, S.N.,Petersen, J.,Pop-Damkov, P.,Sha, L.,Simpson, I.,Tavakoli, S.,Tentarelli, S.,Wang, H.,Ye, Q.,Zheng, X. Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors. J.Med.Chem., 67:20799-20826, 2024 Cited by PubMed Abstract: Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2. We subsequently used structure-based drug design to further improve the potency of this series, ultimately achieving an inhibitor with an IC value of 12 nM. Many compounds in this series were designed to behave as prodrugs, releasing their payload with up to 4-fold improved oral exposure relative to the parent. Subtle stereochemical differences between these various inhibitors and prodrugs had substantial effects on potency and pharmacokinetics. PubMed: 39540340DOI: 10.1021/acs.jmedchem.4c02295 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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