| Structural highlights
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.[1] [2]
Function
ARGI1_HUMAN
Publication Abstract from PubMed
Inhibiting Arginase 1 (ARG1), a metalloenzyme that hydrolyzes l-arginine in the urea cycle, has been demonstrated as a promising therapeutic avenue in immuno-oncology through the restoration of suppressed immune response in several types of cancers. Most of the currently reported small molecule inhibitors are boronic acid based. Herein, we report the discovery of non-boronic acid ARG1 inhibitors through virtual screening. Biophysical and biochemical methods were used to experimentally profile the hits while X-ray crystallography confirmed a class of trisubstituted pyrrolidine derivatives as optimizable alternatives for the development of novel classes of immuno-oncology agents targeting this enzyme.
Discovery of non-boronic acid Arginase 1 inhibitors through virtual screening and biophysical methods.,Gathiaka S, Palte RL, So SS, Chai X, Richard Miller J, Kuvelkar R, Wen X, Cifelli S, Kreamer A, Liaw A, McLaren DG, Fischer C Bioorg Med Chem Lett. 2023 Feb 21;84:129193. doi: 10.1016/j.bmcl.2023.129193. PMID:36822300[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Uchino T, Haraguchi Y, Aparicio JM, Mizutani N, Higashikawa M, Naitoh H, Mori M, Matsuda I. Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia. Am J Hum Genet. 1992 Dec;51(6):1406-12. PMID:1463019
- ↑ Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, Smit LM, Jakobs C, Matsuda I. Molecular basis of phenotypic variation in patients with argininemia. Hum Genet. 1995 Sep;96(3):255-60. PMID:7649538
- ↑ Gathiaka S, Palte RL, So SS, Chai X, Richard Miller J, Kuvelkar R, Wen X, Cifelli S, Kreamer A, Liaw A, McLaren DG, Fischer C. Discovery of non-boronic acid Arginase 1 inhibitors through virtual screening and biophysical methods. Bioorg Med Chem Lett. 2023 Mar 15;84:129193. PMID:36822300 doi:10.1016/j.bmcl.2023.129193
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