7klm

Human Arginase1 Complexed with Inhibitor Compound 24a

spinqualitylabelsall models 7klm, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7klm is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.27Å Ligands: 0IZ, MN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ARGI1_HUMAN Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:207800; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia. Function ARGI1_HUMAN Publication Abstract from PubMed Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model. Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.,Lu M, Zhang H, Li D, Childers M, Pu Q, Palte RL, Gathiaka S, Lyons TW, Palani A, Fan PW, Spacciapoli P, Miller JR, Cho H, Cheng M, Chakravarthy K, O'Neil J, Eangoor P, Beard A, Kim HY, Sauri J, Gunaydin H, Sloman DL, Siliphaivanh P, Cumming J, Fischer C ACS Med Chem Lett. 2021 Jul 16;12(9):1380-1388. doi:, 10.1021/acsmedchemlett.1c00195. eCollection 2021 Sep 9. PMID:34527178 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Arginase 3D structures

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