In previous years evidence emerged that inferred secondary m

In previous years, evidence emerged that inferred secondary metabolites in plants might exhibit a potential arginase inhibition [36]. In a recent study, Pham and co-workers showed the inhibitory activity of chlorogenic SB1518 (7) and piceatannol (8) (Fig. 3b) on mammalian arginase with IC50s of 10.6 and 12.1μM, respectively 49, 50. The authors also identified that the caffeoyl moiety is crucial for arginase inhibition. The molecular docking demonstrated that the catechol group chelates the cofactor Mn2+ in the active site of arginase and prevents enzymatic activity (Fig. 4d). This study suggested that caffeoyl derivatives could be worthy of development as new arginase inhibitors [49].
Anticancer effects of compounds possessing arginase inhibitory activity Among the natural or synthetic arginase inhibitors, some have been evaluated for their anticancer properties, as presented in Table 1. NOHA (2) is an intermediate in the catalytic reaction of NOS to produce l-citrulline and NO from l-arginine (Fig. 1), and inhibits arginase activity 37, 38. Buga et al. reported that 2 inhibited the Caco-2 human colon carcinoma cell growth, probably owing to arginase inhibition and the subsequent conversion of NOHA to NO, which inhibited ODC activity thereby reducing polyamine production [9]. Compound 2 was also shown to inhibit proliferation of the high-arginase-expressing MDA-MB-468 breast cancer cell line [2]. Treatment with 2 (1mM, 48h) induced apoptosis and stopped MDA-MB-468 cells in the S phase, increased the expression of p21 and decreased spermine production [2]. The authors suggested that, in the MDA-MB-468 cell line, the arginase/polyamine pathway was crucial for cancer cell growth [2]. The potent arginase inhibitor nor-NOHA (3) was also reported to inhibit tumor growth in a dose-dependent manner [26]. This anticancer effect was caused by arginase inhibition and probably mediated by an increased lymphocyte response [26]. Vascular leukocytes (VLCs) are the predominant leukocytes present in ovarian tumors and promote tumor progression [51]. Bak et al. showed that murine VLCs suppressed CD8+ and CD4+ T cell responses and that this immunosuppression was ARG-I-dependent [52]. Treatment with 3 inhibited VLC ARG I activity and reversed functions of CD8 and CD4 T cells [52]. Macrophages are found at most tumor sites and are considered as the predominant infiltrating cells in tumors [53]. They use l-arginine to produce NO and polyamines through NOS and arginase, respectively [11]. The macrophage-released NO kills tumor cells whereas polyamines promote tumor cell growth [11]. Chang et al. demonstrated that inhibiting arginase by l-norvaline (9) (Fig. 3a) downregulated the production of polyamines and reversed the suppression of NO-mediated tumoricidal activity of macrophages [11]. Recently, a small-molecule arginase inhibitor CB-1158 (10) (Fig. 3a), 2-amino-6-borono-2-(1-(2,4-dichlorobenzyl)piperidin-4-yl)hexanoic acid, was developed by Calithera Biosciences, as a new immuno-oncology clinical candidate (http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=589516). This compound was reported to inhibit human arginase (IC50=98nM). The CB-1158 treatment reduced Lewis lung carcinoma (LLC) cell growth by increasing the levels of multiple Th1 T cell, natural killer (NK) cell and M1 macrophage-associated chemokines, cytokines and activation markers in the intact LLC tumor microenvironment [30]. Described as a compound with a high oral bioavailability and good tolerance, 10 has been approved by the FDA for a Phase I clinical trial as a single agent or in combination with immune checkpoint therapy in patients with advanced or metastatic solid tumors (https://clinicaltrials.gov/ct2/show/NCT02903914?term=arginase&rank=4). The authors are expecting that 10 will be the first-in-class arginase inhibitor used as a novel immuno-oncology agent targeting the immunosuppressive effects of infiltrating myeloid-derived suppressor cells (MDSCs) [30].