WO2022204606A1 - Benzo-lipoxin analogues for use in treating proliferative diseases - Google Patents

Abstract

This disclosure relates generally to compositions and methods for treating cancer. This disclosure relates more particularly to compositions and methods suitable for treating cancer that are associated with a high level of neutrophil extracellular traps (NETs).

Description

BENZO-LIPOXIN ANALOGUES FOR USE IN TREATING PROLIFERATIVE DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Applications No. 63/166,335, filed March 26, 2021, which is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE [0002] This disclosure relates generally to compositions and methods for treating cancer. This disclosure relates more particularly to compositions and methods suitable for treating cancer that are associated with a high level of neutrophil extracellular traps (NETs). BACKGROUND OF DISCLOSURE [0003] Tumor microenvironment (TME) is a hostile environment that promotes tumor proliferation and progression. In this toxic milieu, hypoxia and nutrient deprivation promotes inflammation leading to elaboration of inflammatory cytokines, chemokines and bioactive lipids which can further promote and sustain tumor survival and proliferation. Tumor- associated inflammation is a key hallmark in tumorigenesis, survival, and progression. The ability to resolve tumorigenic inflammation can block inflammatory mediators which are critical to sustain cancer survival and proliferation. This is the case in a number of cancers which harbor a hyper-inflammatory and pro-tumorigenic TME. Current treatment options for such cancers have limited effectiveness and is associated with adverse side effects. [0004] Neutrophils, the most abundant innate effector cells, serve as first-line defenders against foreign antigenic intrusion. Whereas neutrophils are vital in protecting against microbial pathogens and in healing injured tissues, the inability to clear apoptotic neutrophils can sustain chronic inflammation and (paradoxically) promote tissue injury and autoimmunity. Normally, activated neutrophils are recruited to and sequester in infected or damaged tissues, undergo apoptosis, and are cleared by macrophages through non- phlogistic phagocytosis. However, in the presence of proinflammatory cytokines, neutrophil lifespan is extended, thereby sustaining inflammation. Upon appropriate stimulation, these neutrophils expel their DNA contents as neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, a process known as NETosis. [0005] Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models. For example, NETs were shown to be abundant in the liver metastases of patients with breast and colon cancers and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a ‘trap’ for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. [0006] NETosis is triggered by antigenic or cytokine signals. The attendant increase in NADPH oxidase (NOX-2, encoded by the CYBB gene in humans and the Cybb gene in mice) and toll-like receptor 7 (TLR7), leads to generation of reactive oxygen species (ROS). This oxidative burst leads to the nuclear translocation of neutrophil elastase (NE) and myeloperoxidase (MPO) which, in turn, activates peptidyl arginine deiminase-4 (PAD-4, encoded by the PADI4 gene in humans and the Padi4 gene in mice). PAD-4, the only known PAD to contain a nuclear translocation signal, catalyzes the deiminization of arginine to citrulline residues on histones, thereby promoting chromatin decondensation and unwinding. The ROS burst also activates MEK/ERK phosphorylation and promotes chromatin disassembly and release. NETs elaborated in theTME are able to promote invasion and metastases through the secretion of proteases (e.g., matrix metalloproteinases) and proinflammatory cytokines. The ability to inhibit neutrophil recruitment, activation and elimination NETs in TME may be an effective strategy to treat cancer. . [0007] In addition to the inflammation-sustaining properties of many cytokines and chemokines, certain lipids, such as arachidonic acid and its metabolites prostaglandins and leukotrienes also contribute to the inflammatory process. Counterbalancing these are specialized pro-resolving mediators (SPMs), such as lipoxins (LXs) which mediate resolution of inflammation by promoting non-phlogistic phagocytosis by macrophages of apoptotic polymorphonuclear (PMN) cells. [0008] Lipoxin A4 (LXA₄) is an endogenous bioactive lipid belonging in a SPM. This bioactive lipid is biosynthesized via transcellular metabolism. Unlike other bioactive inflammatory lipids like prostaglandins, leukotrienes and thromboxanes, LXA₄ has potent anti-inflammatory and pro-resolving properties. However, LXA₄ is short-lived in the body which greatly limits its therapeutic potential. [0009] Therefore, there remains a need for anticancer therapy, particularly of cancers that have a hyper-inflammatory and/or pro-tumorigenic TME, using alternative pharmacologic strategies. SUMMARY OF THE DISCLOSURE [0010] One aspect of the disclosure provides a method for treating cancer. Such method includes administering to a subject an effective amount of a benzo-lipoxin analogue, wherein the subject has a high level of neutrophil extracellular traps (NETs). [0011] Another aspect of the disclosure provides a method for inhibiting metastasis of cancer cells. Such method includes administering to the cancer cells an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit metastasis of the cancer cells. [0012] Another aspect of the disclosure provides a method of inhibiting myeloid derived suppressor cells (MDSCs). Such method includes administering to the MDSCs an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit MDSCs. BRIEF DESCRIPTION OF THE DRAWINGS [0013] The accompanying drawings are included to provide a further understanding of the methods and compositions of the disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiment(s) of the disclosure, and together with the description serve to explain the principles and operation of the disclosure. [0014] Figure 1 illustrates in vitro effect of NAP1051 compared to other ALXR agonists. When compared to lipoxin (ATLA) (A), NAP1051 was able to inhibit neutrophil migration towards fMLP (B). In macrophage efferocytosis assays (C), NAP1051 is able to phagocytose apoptotic neutrophils as effectively as ATLA. *: p<0.05; **: p<0.01; ***: p<0.001, ****: p<0.0001. [0015] Figure 2 illustrates molecular effect of ATLA, W-Peptide and NAP1051 on ERK1/2 and AKT pathway in THP-1 (A). In addition, time course analyses of THP-1 treated with 1 ^0^1$3^^^^^DORQJ^WKH^(5.^^^^DQG^$.7^SDWKZD\^(B). In panel (C), NAP1051 promotes p- AKT that is independent of both MEK and PI3K, where inhibition of these pathways using PD98059 and LY294002, did not reduce NAP1051-mediated p-AKT. [0016] Figure 3 illustrates antitumor activity of NAP1051 were evaluated in CT26, colorectal cancer (CRC) implanted into Balb-c immunocompetent mice. A dosage dependent reduction in tumor volumes was observed in animals treated with NAP1051 (e.g., 2.5 and 5.0 mg/kg/day) (A and B). Flow cytometry of immune cells from the spleen (C-E) and tumor (F- H) was evaluated over dosage. [0017] Figure 4 illustrates tumor immunofluorescence staining with DAPI (blue) (A), anti- CitH3 (green) (B), and anti-Ly6G (red) (C) and the merge (D). Arrows identify neutrophils found in the tumor sections. Quantification of neutrophils used Ly6G+, where increasing dosages of NAP1051 reduced the number of neutrophils (E) in the tissue. The expression of PAD4 in neutrophils were reduced by increasing dosages of NAP1051 (F). These finding correlated with reduction in anti-CitH3 staining in tumor tissue (G). *: p < 0.05, **: p <0.01. [0018] Figure 5 illustrates in vitro effect of NAP1051 compared to SPNC 074 and SPNC 080 (A) and to NAP1053 (B). *: p < 0.05, **: p <0.01. DETAILED DESCRIPTION [0019] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to specific embodiments, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. [0020] In view of the present disclosure, the methods and compositions described herein can be configured by the person of ordinary skill in the art to meet the desired need. In general, the disclosed materials and methods provide improvements in treatment of cancer. [0021] The inventors found that the benzo-lipoxin analogues of the disclosure, such as NAP1051, are able to inhibit fMLP-mediated neutrophil chemotaxis, promote neutrophil apoptosis and activate macrophage mediated efferocytosis of apoptotic neutrophil. The inventors also found that the benzo-lipoxin analogues of the disclosure, such as NAP1051, can mediate antitumor activity by inhibiting neutrophil infiltration and/or neutrophil sequestration in the tumor tissue. In certain embodiments, the neutrophils express PAD4. [0022] The inventors also found that the benzo-lipoxin analogues of the disclosure, such as NAP1051, are able to promote macrophage phosphorylation of ERK1/2 and AKT at both serine 473 and threonine 308 and phosphorylation of AKT that is independent of PI3K pathways. NAP1051 is also able to phosphorylate AKT at T308, which was different than lipoxin (ATLA) suggesting a distinctive biological activity different from ATLA. In addition, NAP1051 is also able to inhibit citrullination of histones. [0023] Thus, one aspect of the disclosure provides a method for treating cancer. Such method includes administering to a subject an effective amount of a benzo-lipoxin analogue, wherein the subject has a high level of neutrophil extracellular traps (NETs). The level of NETs may be compared to a reference standard or control. The reference standard or control amount can be established based upon comparative measurements between apparently healthy subjects and subjects with cancer or between uninvolved tissues and malignant tissues. [0024] In certain embodiments, the high level of NETs is a level at least 5% higher than a reference standard or control. In certain embodiments, the high level of NETs is a level at least 10% higher, or at least 50% higher, or at least 100% higher than a reference standard or control. In certain embodiments, the high level of NETs is a level at least 20% higher, or at least 30% higher, or at least 40% higher, or at least 60% higher, or at least 70% higher, or at least 80% higher, or at least 90% higher, or at least 95% higher than a reference standard or control. [0025] NETs consist of chromatin DNA filaments coated with granule proteins. NETs are released by neutrophils to trap microorganisms or in response to tissue injury, and have been associated with cancer metastasis in mouse models, are abundant in the liver metastases of patients with breast and colon cancers. Further, serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a ‘trap’ for them. In several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. [0026] In certain embodiments, the neutrophils as described herein express peptidyl arginine deiminase-4 (PAD4). [0027] Another aspect of the disclosure provides a method of inhibiting metastasis of cancer cells. Such method includes administering to the cancer cells an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit metastasis of the cancer cells. [0028] For example, in one embodiment, the effective amount of the benzo-lipoxin analogue is an amount sufficient to inhibit migration and/or adhesion of the cancer cells. [0029] The benzo-lipoxin analogues of the disclosure, such as NAP1051, are able to inhibit myeloid derived suppressor cells (MDSC). Thus, another aspect of the disclosure provides a method of inhibiting MDSCs. Such method includes administering to the MDSCs an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit MDSCs. [0030] The benzo-lipoxin analogues of the disclosure as described herein are particularly useful in treating of non-small cell lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, and small-cell lung cancer. [0031] In certain embodiments, the cancer is colorectal cancer, breast cancer, pancreatic cancer, non-small cell lung cancer, or prostate cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is non- small cell lung cancer. In certain embodiments, the cancer is prostate cancer. [0032] The cancer, in certain embodiments, is metastatic cancer. [0033] The benzo-lipoxin analogue of the disclosure as described herein may be administered orally, parenterally, intraocularly or by intravitreal administration, intrathecally, or transdermally . In certain embodiments, the administration is oral. In certain embodiments, the administration is parenteral. In certain embodiments, the administration is intraocular or by intravitreal administration. In certain embodiments, the administration is intrathecal. In certain embodiments, the administration is transdermal. [0034] Despite its therapeutic benefits, as noted above, LXA₄ is short-lived in the body which greatly limits its therapeutic potential. The inventors then developed a novel LXA₄ biomimetic, NAP1051, a benzo-lipoxin with increased chemical stability and longer systemic half-life. In addition, NAP1051 retains the biological activities similar to LXA₄, which were affirmed using in vitro assays and in vivo xenograft tumor models. Thus, in certain embodiments, the benzo-lipoxin analogue of the disclosure is NAP1051, or a pharmaceutically acceptable salt thereof. NAP1051 is methyl (5S,6R,E)-5,6-dihydroxy-8-(3- ((R,E)-3-hydroxyoct-1-en-1-yl)phenyl)oct-7-enoate, having the following structure:

[0035] In certain embodiments, the benzo-lipoxin analogue of the disclosure is selected from:

);

; or a pharmaceutically acceptable salt thereof. [0036] In certain embodiments, the benzo-lipoxin analogue of the disclosure is selected from:

and pharmaceutically acceptable salts thereof. [0037] In certain embodiments, the benzo-lipoxin analogue of the disclosure is a compound of formula (1)-(6):

or a pharmaceutically acceptable salt thereof, wherein m is one or two; n is zero, one or two; R^a, R^b, and R^c are independently selected from a group costing of hydrogen, alkyl, aryl, heteroaryl, acyl, and alkoxyacyl; A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or -OM, where M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation; and W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, amido, or sulfonamido. [0038] In certain embodiments, W is alkyl or aryloxy. In certain other embodiments, W is butyl. [0039] In certain embodiments, A is hydroxy or alkoxy (such as methoxy). [0040] In certain embodiments, the benzo-lipoxin analogue of the disclosure is selected from:

and pharmaceutically acceptable salts thereof. For example, in certain embodiments, A is hydroxy or alkoxy (such as methoxy). [0041] In certain embodiments, the benzo-lipoxin analogue of the disclosure is selected from: ,

-ep _{4 ,} -ep ₄ , alkyl esters thereof, and/or pharmaceutically acceptable salts thereof. In certain embodiments, the alkyl ester is a methyl ester. [0042] The benzo-lipoxin analogues of the disclosure may be administered as pharmaceutical compositions comprising the benzo-lipoxin analogue as described herein and an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use. The composition may optionally include one or more secondary therapeutic agents. In certain embodiments, the composition may include one or more anticancer agents or anti- inflammatory agents. [0043] The benzo-lipoxin analogues and the secondary therapeutic agents can be formulated as separate compositions that are given simultaneously or sequentially, or the therapeutic agents can be given as a single composition. In certain embodiments, the secondary therapeutic agent may be administered in an amount below its established half maximal inhibitory concentration (IC₅₀). For example, the secondary therapeutic agent may be administered in an amount less than 1% of, e.g., less than 10%, or less than 25%, or less than 50%, or less than 75%, or even less than 90% of the IC₅₀. [0044] Thus, in certain embodiments, the methods of the disclosure also include administering one or more secondary therapeutic agents. In certain embodiments, the one or more secondary therapeutic agents is anti-inflammatory or anticancer therapeutic agent. [0045] When used to treat or prevent such diseases, the compounds described herein may be administered singly, as mixtures of one or more compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. [0046] Pharmaceutical compositions comprising the benzo-lipoxin analogue(s) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. [0047] The compounds may be formulated in the pharmaceutical composition per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed. [0048] Pharmaceutical compositions may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or [0049] The compound(s) described herein, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. Therapeutic benefit also generally includes halting or slowing the progression of the disease, regardless of whether improvement is realized. [0050] The amount of compound(s) administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular compound(s) the conversation rate and efficiency into active drug compound under the selected route of administration, etc. [0051] Determination of an effective dosage of compound(s) for a particular use and mode of administration is well within the capabilities of those skilled in the art. Effective dosages may be estimated initially from in vitro activity and metabolism assays. For example, an initial dosage of compound for use in animals may be formulated to achieve a circulating blood or serum concentration of the metabolite active compound that is at or above an IC₅₀ of the particular compound as measured in as in vitro assay. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound via the desired route of administration is well within the capabilities of skilled artisans. Initial dosages of compound can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of the active metabolites to treat or prevent the various diseases described above are well-known in the art. Animal models suitable for testing the bioavailability and/or metabolism of compounds into active metabolites are also well-known. Ordinarily skilled artisans can routinely adapt such information to determine dosages of particular compounds suitable for human administration. [0052] Dosage amounts will typically be in the range of from about 0.0001 mg/kg/day, 0.001 mg/kg/day or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the active compound, the bioavailability of the compound, its metabolism kinetics and other pharmacokinetic properties, the mode of administration and various other factors, discussed above. Dosage amount and interval may metabolite compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of compound(s) and/or active metabolite compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective dosages without undue experimentation. Definitions [0053] Throughout this specification, unless the context requires otherwise, the word “comprise” and “include” and variations (e.g., “comprises,” “comprising,” “includes,” “including”) will be understood to imply the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other integer or step or group of integers or steps. [0054] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. [0055] The following terms and expressions used herein have the indicated meanings. [0056] Terms used herein may be preceded and/or followed by a single dash,

”, or a double dash, “=“, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” (i.e., the attachment is via the last portion of the name) unless a dash indicates otherwise. For example, C₁-C₆alkoxycarbonyloxy and -OC(O)C₁-C₆alkyl indicate the same functionality; similarly arylalkyl and –alkylaryl indicate the same functionality. [0057] The term “acyl” as used herein means a –COR group where R is alkyl as defined herein. [0058] The term “alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2- methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl. In certain embodiments, the alkenyl contains from 2 to 6 carbon atoms. [0059] The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. [0060] The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH₂-, -CH₂CH₂-, -CH₂CH₂CHC(CH₃)-, and-CH₂CH(CH₂CH₃)CH₂-. In certain embodiments, the alkyl contains from 1 to 6 carbon atoms. [0061] The term “alkynyl” as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. In certain embodiments, the alkynyl contains from 2 to 6 carbon atoms. [0062] The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4- yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8- tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7- yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H- benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl, 2H- benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6- yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin- 2(1H)-on-5-yl, quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl, quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the aryl is phenyl or naphthyl. In certain other embodiments, the aryl is phenyl. [0063] The term “aryloxy” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy. [0064] The term “carboxy” as used herein means a –CO₂H group. [0065] The term “cycloalkyl” as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH₂)_w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. [0066] The term “halo” or “halogen” as used herein, means -Cl, -Br, -I or -F. [0067] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms. [0068] The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin- 2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8- tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, 2,3- dihydrothieno[3,4-b][1,4]dioxan-5-yl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. [0069] The terms “heterocyclyl” and “heterocycloalkyl” as used herein, mean a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. [0070] The term “oxo” as used herein means a =O group. [0071] The term “saturated” as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like. [0072] The term "substituted", as used herein, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which can be replaced with the radical of a suitable substituent. [0073] The phrase "one or more” substituents, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be either the same or different. As used herein, the term "independently selected" means that the same or different values may be selected for multiple instances of a given variable in a single compound. [0074] The term “thia” as used herein means a =S group. [0075] The term “unsaturated” as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like. [0076] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. Both the R and the S stereochemical isomers, as well as all mixtures thereof, are included within the scope of the disclosure. [0077] “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio or which have otherwise been approved by the United States Food and [0078] “Pharmaceutically acceptable salt” refers to both acid and base addition salts. [0079] “Therapeutically effective amount” or “effective amount” refers to that amount of a compound which, when administered to a subject, is sufficient to effect treatment for a disease or disorder described herein. The amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art. [0080] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, preferably a human, and includes: i. inhibiting a disease or disorder, i.e., arresting its development; ii. relieving a disease or disorder, i.e., causing regression of the disorder; iii. slowing progression of the disorder; and/or iv. inhibiting, relieving, ameliorating, or slowing progression of one or more symptoms of the disease or disorder. [0081] “Subject” refers to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and disorders described herein. EXAMPLES [0082] The methods and compositions of the disclosure are illustrated further by the following examples, which are not to be construed as limiting the disclosure in scope or spirit to the specific procedures and compounds described in them. Example 1: Preparation of NAP1051 [0083] NAP1051 (methyl (5S,6R,E)-5,6-dihydroxy-8-(3-((R,E)-3-hydroxyoct-1-en-1- yl)phenyl)oct-7-enoate) is prepared as disclosed in Scheme 4 and Example 2 of U.S. Patent Application Publication 2005/0203184 A1 and U.S. Patent 9,573,880 B2, both of which are incorporated herein in their entirety. Representative synthetic procedure is provided below.

Example 2: Characterizing the Biological Activity of Lipoxin-Like Analogues [0084] The pharmacologic activity of NAP1051 was evaluated and compared with aspirin trigger lipoxin (ATLA) with regards to its ability to inhibit neutrophil migration towards N- formyl-methionyl-leucyl-phenylalanine (fMLP), a neutrophil chemotactic factor. [0085] To determine whether these chemical entities preserve activities as compared to ATLA, the benzo-lipoxin analogues were screened using two biologically relevant assays: 1) inhibition of fMLP neutrophil chemotaxis assays, and 2) promotion of macrophage mediated efferocytosis of apoptotic neutrophils. 1) Inhibition of Neutrophil Migration towards Chemotactic Factor (fMLP) [0086] Using promyelocyte cell line, HL-60, which was differentiated using 1.3% dimethyl sulfoxide (DMSO) for five days. The ability of NAP1051 to block neutrophil migration towards fMLP was compared to ALTA (Figure 1A versus Figure 1B), where at 1 nM NAP1051 fMLP migration was reduced to 50% as compared to untreated cells. When compared to ATLA, 1 nM NAP1051 was more potent than 100 nM ALTA for this biological test. 2) Macrophage Efferocytosis Assays [0087] The ability of NAP1051 to eliminate apoptotic neutrophils was also evaluated by adding apoptotic neutrophils into cultures containing differentiated THP-1, monocytic cell line, to determine for efferocytosis activity. An efferocytosis index was calculated by quantification of fluorescence area per dTHP-1 cell in relations to apoptotic neutrophils. Apoptotic neutrophils were added into cultures containing dTHP-1 stimulated with 100 nM PMA, where 4 hours after co-incubation, the ability to phagocytose apoptotic neutrophils was evaluated in cells treated with NAP1051 and ATLA (Figure 1C). When compared to no treatment, NAP1051 was able to show increase ability to phagocytose apoptotic neutrophils. Compared to the positive control, 1 μM ATLA, NAP1051 appear to be equipotent in its ability to promote efferocytosis. [0088] Similar to ATLA, an ALXR agonist, benzo-lipoxin analogue, NAP1051, was found to be more potent in inhibiting fMLP-neutrophil chemotaxis. In addition, benzo- lipoxin analogues like NAP1051 can promote efferocytosis in differentiated monocytic cells (dTHP- 1). NAP1051 was equipotent to ATLA in its ability to promote phagocytosis of apoptotic neutrophils. Example 3: Molecular Pathways Associated with NAP1051 [0089] dTHP-1 cells treated with ATLA, W-Peptide or NAP1051, Western blot revealed that NAP1051 was able to more potently phosphorylation of ERK1/2 (p-ERK1/2) and AKT (p- AKT) as compared to ATLA or W-peptide (Figure 2A). The phosphorylation of these targets was time dependent, where by 30 minutes p-ERK1/2 and pAKT was at its highest (Figure 2B). Unexpectedly, NAP1051 was able to phosphorylate AKT (T308), which was not seen for other ALXR agonist, ALTA and W-peptide (Figure 2A). NAP1051 mediated phosphorylation is time dependent as seen in Figure 2B. NAP1051 mediated phosphorylation of AKT (T308) was blocked by LY294002 (PI3K inhibitor) alone. The addition of PD98059 (MEK inhibitor) cause reduction in p-ERK1/2 but no changes in p- AKT was seen for untreated versus 1 μM NAP1051. However, when both LY294002 and PD98059 were added, phosphorylation of p-AKT at both S473 and T308 were shown. This suggest when compared to untreated THP-1 and 1 μM NAP1051 can phosphorylate AKT using both a MEK and PI3K pathways (Figure 2C). Example 4: Significant Inhibition was shown by NAP1051 [0090] The antitumor properties of NAP1051 were evaluated in dosage escalation design in Balb-c (immunocompetent) xenografted with CT26 (colorectal cancer) tumor model. Mice were stratified to receive either oral daily dosages of vehicle, 2.5 or 5.0 mg/kg/day of NAP1051, where after 21 days of treatment, a dosage dependent reduction in tumor volume was shown (Figures 3A and 3B), where animals treated with 5 mg/kg/day of NAP1051 showed significant reduction in tumor volumes as compared to vehicle. [0091] Flow cytometry analysis of immune cellular content found in the spleen (Figure 3C-E) and tumor (Figure 3F-H). This antitumor activity correlated with reduction in splenic myeloid derived suppressor cells (MDSC) and neutrophils (Figure 3E). These finding also correlated with reduction of intratumoral of MDSC and neutrophils (Ly6G+) (Figure 3H). Example 5: Intratumoral Analyses [0092] Additional analyses used tumor sections from treated mice. These sections were stained with antibodies directed against LyG6+ (neutrophils), which affirm that NAP1051 can mediate a dosage dependent reduction in neutrophil infiltration in the tumors (Figure 4C and 4E). Because neutrophils have been associated with neutrophil extracellular traps (NETs), the inventors evaluated whether intratumor Ly6G+ cells expressed peptidyl deiminase-4 (PAD4), an important mediator of inflammation. In Figure 4F, NAP1051 treatment was able to reduce Ly6G+ PAD4+ and Ly6G+ with citrullinated histone 3 (CitH3) cells found in tumor sections (Figure 4 E-G). These findings show that NAP1051 is able to inhibit tumor proliferation through decreasing neutrophil migration into the tumor, and thus prevent activation PAD4, an enzyme that catalyzes deaminating arginine residuals. Analyses determining the level of citrullinated histones (CitH3), showed that NAP1051 is able to reduce Ly6G+CitH3+ intratumoral neutrophils. These findings suggest that NAP1051 can inhibit chromatin decondensation and unwinding, which is thought to further sustain chronic inflammation. Since NAP1051 is able to reduce PAD4+ neutrophil infiltration in the tumors which coincides with reduction in CitH3+ Ly6G+ cells (Figure 4G), these findings suggest that benzo-lipoxin analogues may exert their antitumor properties by eliminating neutrophils and neutrophil extracellular traps. Example 6: ALX/FPR2 Binding Study with AutoDock Vina [0093] Human formyl peptide receptor 2 (FPR2) complex with WKYMVm (W- peptide) was used as the prototype compound binding as described by Chen et al. (Nat Commun., 2020, 11:1208). After the atomic coordinates of the WKYMVm ligand was aligned, the W-peptide was removed. The remaining FPR2 crystal structure served as the receptor for this molecular docking analysis after further optimizations using instructions from the User Manual of AudoDock Vina software (v.1.2.0, open source available from the Scripps Research Institute, La Jolla, California). [0094] The 3D structure of NAP1051 was generated with ChemDraw and optimized using AutoDock Tools software. Docking of NAP1051 onto FPR2 was performed with AutoDock Vina software, as follows: a region of 24,000 Angstom³ centered around the known binding site of WKYMVm was defined as the search space; the binding pose of NAP1051 was identified based on the top-scoring conformation output by the AutoDock Vina algorithm, evaluated in terms of predicted free energy of binding (-kcal/mol); and interactions between NAP1051 and FPR2 were analyzed using the LigPlot+ software. [0095] NAP1051 and several other compounds were evaluated, and their predicted free energy of binding is provided in Table 1. Table 1.

[0096] Comparison of the compounds’ predicted free energy of binding (kcal/mol) was found to correlate to their respective in vitro activities, for example as disclosed by Serhan et al. (Biochemistry 1995, 34(44): 14609–14615). Figure 5 illustrates in vitro effect of NAP1051 compared to SPNC 074 and SPNC 080 (A) and to NAP1053 (B), and these in vitro activity shows good correlation with the compounds’ predicted free energy of binding. [0097] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated herein by reference for all purposes.

Claims

What is claimed is: 1. A method for treating cancer, the method comprising administering to a subject an effective amount of a benzo-lipoxin analogue, wherein the subject has a high level of neutrophil extracellular traps (NETs).

2. A method of inhibiting metastasis of cancer cells, the method comprising administering to the cancer cells an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit metastasis of the cancer cells.

3. The method of claim 2, wherein the effective amount is an amount sufficient to inhibit migration and/or adhesion of the cancer cells.

4. The method according to any of claims 1 to 3, wherein the cancer is selected from the group consisting of non-small cell lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, and small-cell lung cancer.

5. The method according to any of claims 1 to 3, wherein the cancer is colorectal cancer.

6. The method according to any of claims 1 to 3, wherein the cancer is breast cancer.

7. The method according to any of claims 1 to 3, wherein the cancer is pancreatic cancer.

8. The method according to any of claims 1 to 3, wherein the cancer is non-small cell lung cancer.

9. The method according to any of claims 1 to 3, wherein the cancer is prostate cancer.

10. The method according to any of claims 1 to 9, wherein the cancer is metastatic.

11. A method of inhibiting myeloid derived suppressor cells (MDSCs), the method comprising administering to the MDSCs an effective amount of a benzo-lipoxin analogue, and wherein the effective amount is an amount sufficient to inhibit MDSCs.

12. The method according to any of claims 1 to 11, wherein the benzo-lipoxin analogue is

_{pharmaceutically acceptable salt} thereof.

13. The method according to any of claims 1 to 11, wherein the benzo-lipoxin analogue is selected from:

or a pharmaceutically acceptable salt thereof.

14. The method according to any of claims 1 to 11, wherein the benzo-lipoxin analogue is selected from:

and pharmaceutically acceptable salts thereof.

15. The method according to any of claims 1 to 11, wherein the benzo-lipoxin analogue is a compound of formula (1)-(6):

or a pharmaceutically acceptable salt thereof, wherein m is one or two; n is zero, one or two; _R ^{a, Rb, and Rc are independently selected from a group costing of hydrogen, alkyl, aryl,} heteroaryl, acyl, and alkoxyacyl; A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or -OM, where M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation; and W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, amido, or sulfonamido.

16. The method according to claim 14, wherein W is alkyl or aryloxy.

17. The method according to claim 14, wherein W is butyl.

18. The method according to any of claims 14 to 17, wherein A is hydroxy or alkoxy.

19. The method according to claim 14 or 18, wherein the benzo-lipoxin analogue is selected from: ,

, , and pharmaceutically acceptable salts thereof.

20. The method according to any of claims 1 to 19, wherein a high level of NETs is a level at least 5% higher than a reference standard or control.

21. The method according to any of claims 1 to 19, wherein a high level of NETs is a level at least 10% higher, or at least 50% higher, or at least 100% higher than a reference

22. The method according to any of claims 1 to 21, wherein the neutrophils express peptidyl arginine deiminase-4 (PAD4).

23. The method according to any of claims 1 to 22, further comprising administering one or more secondary therapeutic agents.

24. The method of claim 23, wherein the one or more secondary therapeutic agents is an anti-inflammatory agent or an anticancer agent.

25. The method according to any of claims 1 to 24, wherein the benzo-lipoxin analogue is administered orally.

26. The method according to any of claims 1 to 24, wherein the benzo-lipoxin analogue is administered parenterally.

27. The method according to any of claims 1 to 24, wherein the benzo-lipoxin analogue is administered intraocularly or by intravitreal administration.

28. The method according to any of claims 1 to 24, wherein the benzo-lipoxin analogue is administered intrathecally.

29. The method according to any of claims 1 to 24, wherein the benzo-lipoxin analogue is administered transdermally.