6V7C
Human Arginase1 Complexed with Bicyclic Inhibitor Compound 3
Summary for 6V7C
| Entry DOI | 10.2210/pdb6v7c/pdb |
| Descriptor | Arginase-1, MANGANESE (II) ION, {3-[(3aR,4S,5S,6aR)-5-azaniumyl-5-carboxyoctahydrocyclopenta[c]pyrrol-2-ium-4-yl]propyl}(trihydroxy)borate(1-), ... (4 entities in total) |
| Functional Keywords | agonist, arg (arginase), bicyclic, immunotherapy, metalloenzyme, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 6 |
| Total formula weight | 210989.31 |
| Authors | Palte, R.L. (deposition date: 2019-12-08, release date: 2020-05-06, Last modification date: 2023-10-11) |
| Primary citation | Mitcheltree, M.J.,Li, D.,Achab, A.,Beard, A.,Chakravarthy, K.,Cheng, M.,Cho, H.,Eangoor, P.,Fan, P.,Gathiaka, S.,Kim, H.Y.,Lesburg, C.A.,Lyons, T.W.,Martinot, T.A.,Miller, J.R.,McMinn, S.,O'Neil, J.,Palani, A.,Palte, R.L.,Sauri, J.,Sloman, D.L.,Zhang, H.,Cumming, J.N.,Fischer, C. Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy. Acs Med.Chem.Lett., 11:582-588, 2020 Cited by PubMed Abstract: The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, , when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored. PubMed: 32292567DOI: 10.1021/acsmedchemlett.0c00058 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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