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6v7e

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Human Arginase1 Complexed with Bicyclic Inhibitor Compound 12

Structural highlights

6v7e 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 1.99Å
Ligands:	,
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.^[1] ^[2]

Function

ARGI1_HUMAN

Publication Abstract from PubMed

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, 3, 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.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.,Mitcheltree MJ, Li D, Achab A, Beard A, Chakravarthy K, Cheng M, Cho H, Eangoor P, Fan P, Gathiaka S, Kim HY, Lesburg CA, Lyons TW, Martinot TA, Miller JR, McMinn S, O'Neil J, Palani A, Palte RL, Sauri J, Sloman DL, Zhang H, Cumming JN, Fischer C ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. doi:, 10.1021/acsmedchemlett.0c00058. eCollection 2020 Apr 9. PMID:32292567^[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
↑ Mitcheltree MJ, Li D, Achab A, Beard A, Chakravarthy K, Cheng M, Cho H, Eangoor P, Fan P, Gathiaka S, Kim HY, Lesburg CA, Lyons TW, Martinot TA, Miller JR, McMinn S, O'Neil J, Palani A, Palte RL, Saurí J, Sloman DL, Zhang H, Cumming JN, Fischer C. Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy. ACS Med Chem Lett. 2020 Mar 23;11(4):582-588. PMID:32292567 doi:10.1021/acsmedchemlett.0c00058