Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors

Muller, Jason; Cardey, Bruno; Zedet, Andy; Desingle, C.; Grzybowski, Marcin; Pomper, Paulina; Foley, Sarah; Harakat, Dominique; Ramseyer, Christophe; Girard, Christian; Pudlo, Marc

doi:10.1039/d0md00011f

Cited by 9 publications

(8 citation statements)

References 39 publications

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“…Some of the most common plant-derived polyphenols were evaluated regarding their Arg1 inhibitory activity and compared to BEC [ 201 ]. Chlorogenic acid was identified as the most potent among the polyphenols tested ( Figure 6 ), and its catechol moiety was found essential for the competitive inhibitory activity [ 201 , 202 ]. As the replacement of the ketone moiety from chlorogenic acids with a secondary amide improved the stability of the compounds, a series of cinnamide derivatives was developed against Arg1 [ 203 ].…”

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

“…Other experiments with piceatannol glycosides confirmed vasoprotective effects by non-competitive inhibition of arginase [ 206 , 207 ]. More recently, the evaluation of piceatannol analogs without the glycoside side-chain, through quantum chemistry modeling techniques, reiterated the importance of the catechol function for the binding to arginase [ 202 ]. The presence or absence of the glycoside side-chain does not seem to affect the binding affinity of piceatannol significantly, being an ideal position for the potential addition of an imaging moiety.…”

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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Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

Section: Development Of Arginase Inhibitorsmentioning

confidence: 99%

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

Clemente

Waarde

Antunes

et al. 2020

IJMS

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“…11 and inspired from ref. 12 and 13 natural origins are moderate micromolar to millimolar inhibitors. Polyphenols also suffer from fast metabolism, 14 and prolonged release via prodrugs is currently being developed to overcome poor pharmacokinetic parameters.…”

Section: Introductionmentioning

confidence: 99%

A colorimetric assay adapted to fragment screening revealing aurones and chalcones as new arginase inhibitors

Muller,

Marchisio,

Attia

et al. 2024

RSC Med. Chem.

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“…The relevance of ARG1 and ARG2 in cancer, documented by many research groups, has prompted a search for pharmaceutical inhibitors of these enzymes in order to alter the outcome of the immune response and develop new treatment options [ 22 ]. Several natural and synthetic compounds have been evaluated in various tumour models [ 22 , 23 ], of which CB-1158 (numidargistat), predominantly targeting the extracellular ARG1, is the most advanced in clinical development [ 24 ]. The design of competitive arginase inhibitors poses a significant challenge due to the deep and narrow shape of its catalytic pocket.…”

Section: Introductionmentioning

confidence: 99%

OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer

Grzybowski¹,

Stańczak²,

Pomper³

et al. 2022

Cancers

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Background: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets. OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. Methods: The inhibitory activity of OATD-02 was determined using recombinant ARG1 and ARG2, as well as in a cellular system using primary hepatocytes and macrophages. In vivo antitumor activity was determined in syngeneic models of colorectal and kidney carcinomas (CT26 and Renca, respectively), as well as in an ARG2-dependent xenograft model of leukaemia (K562). Results: OATD-02 was shown to be a potent dual (ARG1/ARG2) arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to a reference inhibitor with predominant extracellular activity towards ARG1, we have shown improved and statistically significant antitumor efficacy in the CT26 model and an immunomodulatory effect reflected by Treg inhibition in the Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 effectively inhibited the proliferation of human K562 leukemic cells both in vitro and in vivo. Conclusions: OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022.

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Synthesis, evaluation and molecular modelling of piceatannol analogues as arginase inhibitors

Abstract: A quantum chemistry guided optimisation (leading to piceatannol analogue 3t) with a good understanding of the catechol binding mode to the bimanganese cluster of arginase.

Cited by 9 publications

References 39 publications

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

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

A colorimetric assay adapted to fragment screening revealing aurones and chalcones as new arginase inhibitors

OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer

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