Discovery and Pharmacokinetics of Sulfamides and Guanidines as Potent Human Arginase 1 Inhibitors

Błaszczyk, Roman; Brzezińska, J.; Dymek, Barbara; Stańczak, Paulina Seweryna; Mazurkiewicz, Marcin; Olczak, Jacek; Nowicka, Julita; Dzwonek, Karolina; Zagożdżon, Agnieszka; Gołąb, Jakub; Gołębiowski, Adam

doi:10.1021/acsmedchemlett.9b00508

Cited by 28 publications

(14 citation statements)

References 41 publications

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“…Here, we have used a novel Arg inhibitor (OAT-1746) that blocks both extracellular and intracellular Arg activity and has pharmacokinetic properties allowing for administration twice daily. 38,64 We have observed that OAT-1746 completely restores T-cell proliferation suppressed by recombinant Arg1 added to the culture media. Arg1 suppressed T-cell proliferation (online supplementary figure 6), but did not suppress cytotoxicity effector functions of T-cells and NK cells (online supplementary figure 9).…”

Section: Discussionmentioning

confidence: 94%

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

et al. 2021

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Immunotherapy has demonstrated significant activity in a broad range of cancer types, but still the majority of patients receiving it do not maintain durable therapeutic responses. Amino acid metabolism has been proposed to be involved in the regulation of immune response. Here, we investigated in detail the role of arginase 1 (Arg1) in the modulation of antitumor immune response against poorly immunogenic Lewis lung carcinoma. We observed that tumor progression is associated with an incremental increase in the number of Arg1 + myeloid cells that accumulate in the tumor microenvironment and cause systemic depletion of ʟ-arginine. In advanced tumors, the systemic concentrations of ʟ-arginine are decreased to levels that impair the proliferation of antigen-specific T-cells. Systemic or myeloid-specific Arg1 deletion improves antigen-induced proliferation of adoptively transferred T-cells and leads to inhibition of tumor growth. Arginase inhibitor was demonstrated to modestly inhibit tumor growth when used alone, and to potentiate antitumor effects of anti-PD-1 monoclonal antibodies and STING agonist. The effectiveness of the combination immunotherapy was insufficient to induce complete antitumor responses, but was significantly better than treatment with the checkpoint inhibitor alone. Together, these results indicate that arginase inhibition alone is of modest therapeutic benefit in poorly immunogenic tumors; however, in combination with other treatment strategies it may significantly improve survival outcomes.

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Section: Discussionmentioning

confidence: 94%

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

et al. 2021

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“…This might be explained by the rapid elimination (the mean residence time was 12.5 min) and high clearance owing to hydroxyguanidine chemical and metabolic lability [ 138 ]. Researches have been investigating new arginase inhibitors with characteristics of low clearance, long t1/2, and moderate volume distribution [ 139 ]. In summary, it is very promising that arginase inhibitor might improve endothelium function and attenuate ischemic heart diseases, but it still needs to be further verified by clinical studies (Tables 2 and 3 ).…”

Section: Arginasementioning

confidence: 99%

Neutrophil degranulation and myocardial infarction

Zhang

Aiyasiding

et al. 2022

Cell Commun Signal

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Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Graphical abstract Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP‐8, MMP‐9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP‐8); Matrix metalloproteinase 9 (MMP‐9).

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“…Recent sulfamoyl and guanidinium Cα-substituted ABH analogs, 3 and 4 respectively, have been developed, with the latter compound revealing higher inhibitory potency against Arg1 and improved pharmacokinetic profile (elimination half-life approx. 1 day) [ 172 ]. Compound 4 was also evaluated regarding its enantiomers, showing greater inhibitory potency (approx.…”

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

“…210 times higher) of the R -enantiomer over the S -enantiomer ( Figure 5 ). Nonetheless, tests with the racemic mixture merely doubled the IC 50 when compared to the optimal enantiomeric conformation ( R -enantiomer) [ 172 ], which indicates that extra purification efforts can be skipped, at least for initial proof-of-concept purposes where inactive enantiomers do not affect parallel processes (e.g., if used in trace amounts).…”

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

“…The same biopharmaceutical company developed a novel orally dosed arginase inhibitor CB-280 (undisclosed structure), which already entered phase I trials for the treatment of cystic fibrosis [ 181 ]. Another novel Arg1 and Arg2 inhibitor, OATD-02 by OncoArendi Therapeutics SA (undisclosed structure, IC 50 < 50 nM [ 182 ]), is also expected to enter phase I trials mid-2020 to evaluate its ability to inhibit the proliferation and immune escape of cancer cells [ 172 ]. The combination of third-generation arginase inhibitors with other immune checkpoint inhibitors in a mouse glioma model recently suggested improving therapeutic response [ 183 ], which opens new doors for the development and use of arginase inhibitors.…”

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

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Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

Clemente

Waarde

Antunes

et al. 2020

IJMS

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Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

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Discovery and Pharmacokinetics of Sulfamides and Guanidines as Potent Human Arginase 1 Inhibitors

Cited by 28 publications

References 41 publications

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

Neutrophil degranulation and myocardial infarction

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

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