15-PGDH inhibitors for treating macrophage associated inflammatory disorders and diseases

Abstract

Method of treating an inflammatory disorder or disease characterized by macrophages in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor to treat the inflammatory disorder or disease.In some embodiments, the inflammatory disease is any of arteritis, vascular inflammation, giant cell arteritis, sarcoidosis, rheumatoid arthritis, or other conditions associated with inflammatory macrophages or associated with macrophages and oxidative tissue damage.

Description

PATENT 15-PGDH INHIBITORS FOR TREATING MACROPHAGE ASSOCIATED INFLAMMATORY DISORDERS AND DISEASES RELATED APPLICATION

[0001] This application claims priority from U. S. Provisional ApplicationNo. 63 / 789,160, filed April 15, 2025, the subject matter of which is incorporated herein by reference in its entirety.GOVERNMENT FUNDING

[0002] This invention was made with government support under AG066707, AG071512, AG073323, AG073684, AG083111, CA197442, DA044123, and GM142002 awarded by the National Institutes of Health; and W81XWH-22-1-0129 awarded by the Department of Defense. The government has certain rights in the invention.BACKGROUND

[0003] Short-chain dehydrogenases (SCDs) are a family of dehydrogenases that share only 15% to 30% sequence identity, with similarity predominantly in the coenzyme binding domain and the substrate binding domain. In addition to their role in detoxification of ethanol, SCDs are involved in synthesis and degradation of fatty acids, steroids, and some prostaglandins, and are therefore implicated in a variety of disorders such as lipid storage disease, myopathy, SCD deficiency, and certain genetic disorders.

[0004] The SCD, 15-hydroyxy-prostaglandin dehydrogenase (15-PGDII), represents the key enzyme in the inactivation of a number of active prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) (e.g., by catalyzing oxidation of PGE2to 15-keto-prostaglandin E2, 15k-PGE). The human enzyme is encoded by the HPGD gene and consists of a homodimer with subunits of a size of 29 kDa. The enzyme belongs to the evolutionarily conserved superfamily of short-chain dehydrogenase / reductase enzymes (SDRs), and according to the recently approved nomenclature for human enzymes, it is named SDR36C1. Thus far, two forms of 15-PGDH have been identified, NAD+-dependent type I 15-PGDH and the type II NADP-dependent 15-PGDH, also known as carbonyl reductase 1 (CBR1, SDR21C1). However, the preference of CBR1 for NADP and the high Km values of CBR1 for most prostaglandin suggest that the majority of the in vivo activity can be attributed to type I 15-PGDH.SUMMARY

[0005] Embodiments described herein relate to a method of treating an inflammatory disorder or disease characterized by macrophages in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor to treat the inflammatory disorder or disease.

[0006] In some embodiments, the macrophages express 15-PGDH.

[0007] In some embodiments, the macrophages are associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages.

[0008] In some embodiments, the inflammation is associated with oxidative tissue damage.

[0009] In some embodiments, the inflammatory disease is any of arteritis, vascular inflammation, giant cell arteritis, sarcoidosis, rheumatoid arthritis, or other conditions associated with inflammatory macrophages or associated with macrophages and oxidative tissue damage.

[0010] In some embodiments, the 15-PGDH inhibitor is administered to the subject at an amount effective to block aberrantly increased 15-PGDH enzymatic activity.

[0011] In some embodiments, the 15-PGDH inhibitor is a small molecule that binds to 15-PGDH protein.

[0012] In some embodiments, the 15-PGDH inhibitor can inhibit enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 pM. or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC50 of less than 10 nM, or more preferably at an IC50 of less than 5 nM, or more preferably at an IC50of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.

[0013] In some embodiments, the 15-PGDH inhibitor is a molecule or generates a molecule that binds to 15-PGDH mRNA to promote degradation 15-PGDH mRNA and / or inhibit expression of 15-PGDH.

[0014] In some embodiments, the molecule comprises an RNA interference (RNAi) molecule, preferably at least one of a small interfering RNA (siRNA) or microRNA (miRNA).

[0015] In some embodiments, the 15-PGDH inhibitor comprises an agent or method of gene editing that inactivates or alters the HPGD gene that encodes 15-PGDH.

[0016] In some embodiments, the 15-PGDH inhibitor comprises at least one nuclease that can remove, cut, or alter a target nucleic acid sequence of the HPGD gene.

[0017] In some embodiments, the 15-PGDH inhibitor is an agent that promotes the degradation of 15-PGDH protein.

[0018] In some embodiments, the agent comprises at least one of a small molecule-assisted shutoff (SMASH) system, a Shield- 1 -inducible degron, an auxin inducible degron, an IMid-inducible degron, a peptidic degron, a proteolysis targeting chimera, or an antibody for targeted 15-PGDH degradation.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figs. l(A-B) illustrate images of tissue specimens from patients clinically diagnosed with sarcoidosis evaluated by 15-PGDH immunohistochemistry.

[0020] Figs. 2(A-B) illustrates images of tissue specimens from patients clinically diagnosed with rheumatoid arthritis evaluated by 15-PGDH immunohistochemistry.

[0021] Figs. 3(A-B) illustrate images of specimens from patients clinically diagnosed with giant cell arteritis evaluated by 15-PGDH immunohistochemistry.DETAILED DESCRIPTIONDefinitions

[0022] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0023] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0024] The terms "comprise," "comprising," "include," "including," "have," and "having" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as", "e.g., ", as used herein are non-limiting and are for illustrative purposes only. " Including" and "including but not limited to" are used interchangeably.

[0025] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of suchexclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0026] Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0027] The term “pharmaceutically acceptable’’ means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use within the scope of sound medical judgment.

[0028] The term “pharmaceutically acceptable salt” include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. The term “pharmaceutically acceptable salts” also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like. Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like.

[0029] Additionally, the salts of the compounds described herein, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0030] The term "solvates" means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.

[0031] The compounds and salts described herein can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the present compounds. A tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

[0032] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.

[0033] Tautomerizations can be catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g., an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.

[0034] The terms below, as used herein, have the following meanings, unless indicated otherwise:“Amino” refers to the -NH2radical.“Cyano” refers to the -CN radical.“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo radical.“Hydroxy” or “hydroxyl” refers to the -OH radical.“Imino” refers to the =NH substituent.“Nitro” refers to the -NO2radical.“Oxo” refers to the =0 substituent.“Thioxo” refers to the =S substituent.

[0035] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A Ci-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes C6 alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes Cn and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0036] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Nonlimiting examples of C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0037] “Alkenyl" or “alkenyl group" refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0038] “Alkenylene" or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.

[0039] “Alkynyl” or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, Cs, C9 and C10 alkynyls. Similarly, a C2-C12 alkynyl includes all the foregoing moieties, but also includes Cn and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0040] “Alkynylene" or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non- limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0041] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0042] “Alkylamino” refers to a radical of the formula -NHRaor -NRaRawhere each Rais, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0043] “Alkylcarbonyl” refers to the -C(=O)Ramoiety, wherein Rais an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety. Alkylcarbonyl groups can also be referred to as “Cw-Czacyl” where w and z depicts the range of the number of carbon in Ra, as defined above. For example, “C1-C10 acyl” refers to alkylcarbonyl group as defined above, where Rais C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.

[0044] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0045] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rc is one or more aryl radicals as defined above.Aralkyl radicals include, but are not limited to, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.

[0046] “Aralkenyl” or “arylalkenyl” refers to a radical of the formula -Rb-Rcwhere Rb is an alkenylene group as defined above and Rcis one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.

[0047] “Aralkynyl” or “arylalkynyl” refers to a radical of the formula -Rb-Rcwhere Rb is an alkynylene group as defined above and Rcis one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.

[0048] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl.Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0049] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0050] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.

[0051] “Cycloalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.

[0052] “Cycloalkylalkyl” refers to a radical of the formula -Rb-Rd where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.

[0053] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0054] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1 -fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0055] “Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1 -fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0056] “Heterocyclyl,” “heterocyclic ring’’ or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, and spiral ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, oextanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopipcridinyl, 2-oxopyrrolidinyl, oxazolidinyl, pipcridinyl, pipcrazinyl, 4-pipcridonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl,1, 1 -dioxo-thiomorpholinyl, pyridine-one, and the like. The point of attachment of the heterocyclyl, heterocyclic ring, or heterocycle to the rest of the molecule by a single bond is through a ring member atom, which can be carbon or nitrogen. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0057] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an alkylene group as defined above and Rcis a heterocyclyl radical as defined above. Unlessstated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.

[0058] “Heterocyclylalkenyl” refers to a radical of the formula -Rb-Rewhere Rb is an alkenylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkenyl group can be optionally substituted.

[0059] “Heterocyclylalkynyl” refers to a radical of the formula -Rb-Re where Rb is an alkynylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkynyl group can be optionally substituted.

[0060] ‘W-heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a < V-helerocyclyl group can be optionally substituted.

[0061] “Heteroaryl” refers to a 5- to 20-membered ring system radical one to thirteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, as the ring member. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems, wherein at least one ring containing a heteroatom ring member is aromatic. The nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, bcnzofuranyl, bcnzooxazolyl, bcnzothiazolyl, bcnzothiadiazolyl, bcnzo[Z?][l,4]dioxcpinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1 -oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl. phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolopyridinc, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0062] “7V-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.

[0063] “Heteroarylalkyl” refers to a radical of the formula -Rb-Rf where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.

[0064] “Heteroarylalkenyl” refers to a radical of the formula -Rb-Rf where Rb is an alkenylene, chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otheiwise specifically in the specification, a heteroarylalkenyl group can be optionally substituted.

[0065] “Heteroarylalkynyl” refers to a radical of the formula -Rb-Rf where Rb is an alkynylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.

[0066] “Thioalkyl” refers to a radical of the formula -SRawhere Rais an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.

[0067] The term “substituted” used herein means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, A^-heterocyclyl, heterocyclylalkyl, heteroaryl, 7V-heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, etc.) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamincs, dialkylamincs, arylamincs, alkylarylamincs, diarylamincs, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replacedwith -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh.“Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, A-heterocyclyl, heterocyclylalkyl, heteroaryl, A^-hclcroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, / -heterocyclyl, heterocyclylalkyl, heteroaryl, A-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0068] As used herein, the symbol “” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. Forexample,indicates that the chemical entity “A” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound&, wherein X is” infers that the point of attachment bond is the bond by which X is depicted as being attached to the phenyl ring at the ortho position relative to fluorine.

[0069] The phrases "parenteral administration" and "administered parenterally" are ait-recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastcmal injection and infusion.

[0070] The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0071] The term "preventing" is art-recognized and includes stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and / or condition but has not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.

[0072] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder.

[0073] The temis "prophylactic” or “therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or otherunwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0074] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" are ait-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. The terms include without limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.

[0075] The phrase "therapeutically effective amount" or “pharmaceutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic agent for in vivo use will likely depend on a number of factors, including: the rate of release of an agent from a polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the agent.

[0076] The term " ED50" is art- recognized. In certain embodiments, ED50 means the dose of a drug, which produces 50% of its maximum response or effect, or alternatively, the dose, which produces a pre-determined response in 50% of test subjects or preparations. The term " LD50" is art-recognized. In certain embodiments, LD50 means the dose of a drug,which is lethal in 50% of test subjects. The term "therapeutic index" is an art-recognized term, which refers to the therapeutic index of a drug, defined as LD50 / ED50.

[0077] The terms " IC50," or “half maximal inhibitory concentration” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.

[0078] " Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.

[0079] The term "or" as used herein should be understood to mean "and / or", unless the context clearly indicates otherwise.

[0080] As used herein, the term "about" or "approximately" refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term "about" or "approximately" refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.

[0081] All percentages and ratios used herein, unless otherwise indicated, arc by weight.

[0082] The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition.

[0083] The term "disease", "disorder", or “condition” is used interchangeably herein, and refers to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person.A disease or disorder can also relate to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, or affectation.

[0084] Embodiments described herein relate to the use of 15-PGDH inhibitors for treating inflammatory conditions associated with or characterized by macrophages including, for example, macrophage derived giant cells and macrophage generated granulomas. As shown and discussed in International Patent Application PCT / US2025 / 035911(WO 2026 / 006830), which is herein incorporated by reference in its entirety, we found that in the brain, macrophage related cells are the primary source of 15-PGDH and that 1 -PGDH positive macrophages are increased in a 5xFAD mouse model of Alzheimer’s disease. Single cell RNA sequencing data showed localization of HPGD transcript encoding 15-PGDH in normal mouse brain was primarily in myeloid cells annotated as microglia and perivascular macrophages (Micro-PVM), in which microglia are understood to be brain equivalents of macrophages. This finding is further supported by data showing HPGD expressing cells are marked by Mrcl, a marker of brain perivascular macrophages, or by TMEM119, a marker of brain microglia and increased in the 5xFAD mouse brain.

[0085] We further found that inhibiting 15-PGDH, either using SW033291, a small molecule 15-PGDH inhibitor, or by genetic knockout of one allele of 15-PGDH, protects the 5xFAD mouse from cognitive decline, protects from ultrastructural damage to the blood brain barrier as assessed by astrocyte end feet swelling, and protects from leakiness of the blood brain barrier as assessed by penetration of immunoglobulin into the brain. We also found that inhibiting 15-PGDH can protect mice subject to traumatic brain injury from neurodegeneration, from damage to the blood brain barrier, and from oxidative damage.

[0086] Additionally, we show that pharmacologic or genetic inhibition of 15-PGDH protects the brain from oxidative damage assessed by staining for 4-HNE and for 3-NT. Moreover, we show that the BV2 microglial cell line can be activated to generate reactive oxygen species when incubated with amyloid beta oligomers that are characteristic of Alzheimer’s disease in man and of the 5x-FAD mouse brain. Generation of reactive oxygen can be blocked by incubating BV2 microglial cells with multiple substrates that 15-PGDH enzymatically degrades and limits, including PGE2, PGF2a, 15-HETE, RvDl, and LXA4 (respectively prostaglandin E2, prostaglandin F2 alpha, 15-HETE, resolving DI, and lipoxin A4).

[0087] These findings demonstrate that inhibiting 15-PGDH blocks damage to the brain by blocking microglial generation of reactive oxygen in 15-PGDH positive microglial cells. In the case of Alzheimer’s disease, the microglial reactive oxygen generation can be stimulated by amyloid beta oligomers.

[0088] We found that this mechanism can be general across multiple macrophage subclasses, with multiple different human macrophage related inflammatory conditions marked by floridly 15-PGDH expressing macrophages. In particular, we found that 15-PGDH positive macrophages, and macrophage derived giant cells, and macrophage generated granulomas, are profusely present and associated with the destructive inflammatory processes of giant cell arteritis, of sarcoidosis, and of rheumatoid arthritis.

[0089] Figs. 1 to 3 show images of representative tissue sections from clinically acquired samples of sarcoidosis, giant cell arteritis and rheumatoid arthritis that were stained with a 15-PGDH antibody.

[0090] Figs l(A-B) show studies of Sarcoidosis. Eleven tissue specimens from patients clinically diagnosed with sarcoidosis were evaluated by 15-PGDH immunohistochemistry. Ten of the samples were lung tissue samples and one was from a gum biopsy. Each specimen contained the characteristic macrophage granulomatous inflammatory pattern of sarcoidosis. In nine of 11 samples, the macrophage granulomatous infiltrate stained intensely positive for 15-PGDH, with representative images of hematoxylin and eosin stained lesions in Fig. 1A and of 15-PGDH immunohistochemistry in Fig. IB.

[0091] Figs. 2(A-B) depict studies of rheumatoid arthritis. Six tissue specimens from patients clinically diagnosed with rheumatoid arthritis were evaluated by 15-PGDH immunohistochemistry. Each sample contained macrophages and activated synovial cells which are tissue macrophages. In all six samples, the macrophage / synovial cells stained positive for 15-PGDH, with representative images of hematoxylin and eosin stained lesions in Fig. 2A and of 15-PGDH immunohistochemistry in Fig. 2B.

[0092] Figs. 3(A-B) depict studies of Giant Cell Arteritis. Five tissue specimens from patients clinically diagnosed with giant cell arteritis were evaluated by 15-PGDH immunohistochemistry. Each sample contained an artery with chronic inflammation with a giant cell macrophage infiltrate. In all five samples, the macrophage cells stained positive for 15-PGDH, with representative images of hematoxylin and eosin stained lesions in Fig. 3A and of 15-PGDH immunohistochemistry in Fig. 3B.

[0093] The above studies are further supported by reanalysis of single cell RNA sequencing data available from lesions of human sarcoid patients and human rheumatoid arthritis patients.

[0094] Single cell RNA sequencing data on cutaneous sarcoid granulomas as compared to the same patients’ non-involved skin was performed in Krausgruber et al., Immunity. 2023 Feb 14;56(2):289-306.e7. doi: 10.1016 / j.immuni.2023.01.014, which is incorporated herein by reference in its entirety. As reported in the paper, sarcoid granulomas are marked by a marked infiltration of two types of macrophages GAO (labeled as macrophage 1 in the online data - GSE 192456) and GAI (labeled as monocyte derived macrophages in the online data-GSE192456). In the disease granulomas, these two cell populations respectively increase 4-fold, (from 2.7% to 10%) and 15-fold (from 0.9% to 13.7%). Our re-analysis of this data identifies that in the granuloma samples, 12.3% and 9.7% of GAO and GAI macrophages are positive for expression of HPGD transcript that encodes 15-PGDH, thus confirming the interpretation of the 15-PGDH immunohistochemistry that a target population of 15-PGDH positive macrophages is present in the sarcoid lesions. By analogy to findings in the murine brain, inhibition of 15-PGDH in these cells are predicted to increase levels of 15-PGDH substrates (PGE2, PGF2a, 15-HETE, RvDl, and LXA4) and to inhibit generation of reactive oxygen species in the macrophage population as a whole, thereby inhibiting the inflammatory progression of the disease. Indeed, reanalysis of this dataset shows that GAO and GAI cells near universally express CYBB, that encodes the catalytic subunit of the NADPH oxidase which is the principal source of macrophage generated reactive oxygen (96% and 97% CYBB positivity respectively) and account for 82% of all CYBB expression in the granuloma lesions.

[0095] Single cell RNA sequencing data on samples of rheumatoid arthritis affected joints (validation cohort 1 / cohort 2) was similarly performed by Alivernini et al. Nat Med.2020 Aug;26(8):1295-1306. doi: 10.1038 / s41591-020-0939-8, with raw data posted at EMBL-EBI with the accession number E-MT AB-8322. Reanalysis of this data from synovial tissue samples from treatment naive patients again identified HPGD expressing cells, with 60% of these cells identified as macrophages and 14% as fibroblasts (table below).

[0096] This data again supports and confirms the interpretation of our immunohistochemistry studies that rheumatoid arthritis joints include a prominent population of 15-PGDH expressing macrophages along with some synovial fibroblasts. By analogy to findings in the murine brain, inhibition of 15-PGDH in these cells is expected to increase levels of 15-PGDH substrates (PGE2, PGF2a, 15-HETE, RvDl, and LXA4) and to inhibit generation of reactive oxygen species in the macrophage population as a whole, thereby inhibiting the inflammatory progression of the disease. Moreover, further reanalysis of this data also finds that 35% of all macrophage identified cells in this data also express CYBB, which is the hallmark of the reactive oxygen generating NADPH oxidase pathway.Methods of treating inflammatory conditions, diseases, or disorders characterized by macrophages.

[0097] In some embodiments, the inflammatory conditions, diseases and / or disorders characterized by macrophages can be associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages. Inflammatory conditions, diseases and / or disorders characterized by macrophages or associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can also be associated with enhanced or aberrant 15-PGDH activity in a subject.

[0098] In some embodiments, a method of treating inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include administering to the subject an amount of a 15-PGDH inhibitor effective to prevent and / or decrease reactive oxygen species generation and / or oxidative tissue damage and treat the inflammatory conditions, diseases and / or disorders.

[0099] In some embodiments, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include any one of arteritis, vascular inflammation, giant cell arteritis, sarcoidosis, rheumatoid arthritis, or other conditions associated with inflammatory macrophages or associated with macrophages and oxidative tissue damage, such as polymyalgia rheumatica.

[0100] For example, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include variable vessel vasculitis (VVV) including Behcet's disease (BD) and Cogan's syndrome (CS), large vessel vasculitis (LVV) including Takayasu arteritis (TAK) and giant cell arteritis (GCA); medium vessel vasculitis (MW) including Polyarteritis nodosa (PAN) and Kawasaki disease (KD); small vessel vasculitis (SVV) including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (such as Microscopic polyangiitis (MPA), granulomatosis with polyangiitis (Wegener's) (GPA), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)) and immune complex SVV (such as Anti-glomerular basement membrane (anti-GBM) disease, cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schanlein) (IgAV), hypocomplementemic urticarial vasculitis (HUV) (anti-Clq vasculitis)); single-organ vasculitis (SOV) including cutaneous leukocytoclastic angiitis, Cutaneous arteritis, Primary central nervous system vasculitis, isolated aortitis; rheumatoid vasculitis, sarcoid vasculitis; or vasculitis associated with probable etiology7including Hepatitis C virus-associated cryoglobulinemic vasculitis, Hepatitis B virus-associated vasculitis, Syphilis-associated aortitis, drug-associated immune complex vasculitis, drug-associated ANCA-associated vasculitis, and cancer-associated vasculitis.

[0101] In other embodiments, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, orwith granulomatous inflammation, or with central necrosis and palisading macrophages can be selected from Behcet's disease (BD), Cogan's syndrome (CS), Takayasu arteritis (TAK), giant cell arteritis (GCA), polyarteritis nodosa (PAN), Kawasaki disease (KD), anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Microscopic polyangiitis (MPA), granulomatosis with polyangiitis (Wegener's) (GPA), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA)), immune complex small vessel vasculitis, anti-glomerular basement membrane (anti-GBM) disease, cryoglobulinemic vasculitis (CV), IgA vasculitis (Henoch-Schanlein) (IgAV), hypocomplementemic urticarial vasculitis (HUV) (anti-Clq vasculitis), vutaneous leukocytoclastic angiitis, cutaneous arteritis, Primary central nervous system vasculitis, isolated aortitis, rheumatoid arthritis, sarcoidosis, or polymyalgia rheumatica.

[0102] In some embodiments, the 15-PGDH inhibitor can be administered to the subject at an amount effective to decrease at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and / or 3 -nitrotyrosine (3-NT) levels, by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or more.

[0103] In some embodiments, the method includes measuring at least one biomarker of reactive oxygen species generation in tissue or blood of the subject and administering to the subject an amount of a 15-PGDH inhibitor effective to decrease reactive oxygen species generation in the tissue or blood of the subject. Methods of measuring reactive oxygen species generation in a tissue can include, for example, measuring 4-hydroxy-2-nonenal (4-HNE) and / or 3 -nitrotyrosine (3-NT) levels as described in Domenico et al., Free Radic. Biol. Med. Ill, 253-261 (2017); Shin et al., Biomedicines 8, 326 (2020); and Sultana, et al., Neurobiol. Dis. 22, 76-87 (2006).

[0104] In some embodiments, the method includes measuring at least one biomarker of reactive oxygen species generation, such as 4-hydroxy-2-nonenal (4-HNE) and / or 3-nitrotyrosine (3-NT) levels, in blood of the subject following administration of the 15-PGDH inhibitor and comparing the measured biomarker of reactive oxygen species generation to a control, wherein a decrease in 4-hydroxy-2-nonenal (4-HNE) and / or 3-nitrotyrosine (3-NT) levels is indicative of efficacy of the 15-PGDH inhibitor in treating inflammatory conditions,diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages in the subject. The control can be, for example, the 4-hydroxy-2-nonenal (4-HNE) and / or 3 -nitrotyrosine (3-NT) levels of the subject prior to administration of the 15-PGDH inhibitor.

[0105] In other embodiments, the method includes measuring 15-PGDH expression levels in macrophages of tissue or blood of the subject and comparing the measured 15-PGDH level to a control level, such the 15-PGDH level of macrophages from a healthy subject, and administering to the subject an amount of a 15-PGDH inhibitor effective to inhibit 15-PGDH activity in macrophages of the tissue or blood of the subject if the measured level is greater than the control level.

[0106] In some embodiments, the method includes measuring 15-PGDH expression levels in macrophages of tissue or blood of the subject following administration of the 15-PGDH inhibitor and comparing the measured 15-PGDH levels to a control level, wherein a decrease in 15-PGDH levels is indicative of efficacy of the 15-PGDH inhibitor in treating inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages in the subject. The control can be, for example, the 15-PGDH levels of a healthy subject or the subject prior to administration of the 15-PGDH inhibitor.

[0107] In some embodiments, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages arc associated with an increase in reactive oxygen species in tissue, such as vascular tissue, of at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% relative to normal or healthy tissue. In certain embodiments, administration of a 15-PGDH inhibitor can be used to decrease reactive oxygen species in tissue of the subject from about 5% to about 200%, about 5% to about 180%, about 5% to about 160%, about 5% to about 140%, about 5% to about 120%, about5% to about 100%, about 5% to about 80%, about 5% to about 60%, about 5% to about 40%, about 10% to about 200%, about 10% to about 180%, about 10% to about 160%, about 10% to about 140%, about 10% to about 120%, about 10% to about 100%, about 10% to about 80%, about 10% to about 60%, about 30% to about 200%, about 30% to about 180%, about 30% to about 160%, about 30% to about 140%, about 30% to about 120%, about 30% to about 100%, about 30% to about 80%, about 40% to about 200%, about 40% to about 180%, about 40% to about 160%, about 40% to about 140%, about 40% to about 120%, about 40% to about 100%, about 50% to about 200%, about 50% to about 180%, about 50% to about 160%, about 50% to about 140%), about 50% to about 120%, about 60% to about 200%, about 60% to about 180%, about 60% to about 160%, about 60% to about 140%, about 70% to about 200%, about 70% to about 180%, about 70% to about 160%, about 80% to about 200%, about 80% to about 180%, or about 80% to about 200%.

[0108] In some embodiments, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages is also associated with an aberrant level (e.g., decrease or increase in the level) of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2a, 6-keto-PGFla, PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET in tissue of the subject. For example, the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can be characterized by an increase or decrease in the level of at least one eicosanoid selected from PGE2, 15-keto-PGE2, PGF2α, 6-keto-PGF1α, PGD2, PGJ2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, 14,15-DHET, or 11,12-DHET of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more in tissue of the subject relative to a normal or healthy subject.

[0109] In some embodiments, the 15-PGDH inhibitor can be administered to the subject to modulate the level of the aberrant eicosanoid to a normal or healthy level in the tissue. For example, the inflammatory conditions, diseases and / or disorders characterized bymacrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can be associated with an increase in the level of at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in tissue (e.g., vascular tissue) of the subject, and the 15-PGDH inhibitor can be administered to the subject at amount effective to decrease the levels of the at least one of 15-keto-PGE2, TN-E, TXB2, LTB4, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 17-HDA, 12, 13-DiHOME, 9,10-DiHOME, or 14,15-DHET in tissue of the subject.Small Molecule 15-PGHD inhibitors

[0110] In some embodiments, small molecule 15-PGDH inhibitors used to treat inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can be identified using assays in which putative inhibitor compounds are applied to cells, e.g., macrophages, expressing 15-PGDH and then the functional effects on 15-PGDH activity are determined. Samples or assays comprising 15-PGDH that are treated with a potential inhibitor are compared to control samples without the inhibitor to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative 15-PGDH activity value of 100%. Inhibition of 15-PGDH is achieved when the 15-PGDH activity value relative to the control is about 80%, optionally 50% or 25%, 10%, 5% or 1%.

[0111] Small molecules tested as 15-PGDH inhibitors can be any small chemical molecule or compound. The assays are designed to screen large chemical libraries by automating the assay steps and providing compounds from any convenient source to assays, which are typically run in parallel (e.g., in microtiter formats on microtiter plates in robotic assays).

[0112] In some embodiments, the 15-PGDH inhibitor can include a compound having the following formula (I):rmaceutically acceptable salt, tautomer, or solvate thereof;wherein n is 0-2;Y1, Y2, and R1are the same or different and are independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl,C6-C24 aralkyl, halo, -Si(Ci-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkcnyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanate, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinate, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein Y1and Y2may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl;U1is N, C-R2, or C-NR3R4, wherein R2is selected from the group consisting of a H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, O-CH2-CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1and R2may be linked to form a cyclic or polycyclic ring, wherein R3and R4are same or different and are each selected from the group consisting of II, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl,Br, or I), CN, (C=O)-R’, (C=O)N(R')2, COOR’ (wherein R’ is H or a lower alkyl group), and R3or R4may be absent;X1and X2are independently N or C, and wherein when X1and / or X2are N, Y1and / or Y2, respectively, are absent; andZ1is O, S, CRaRbor NRa, wherein Raand Rbare independently H or a Ci-s alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted.

[0113] In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (II):pharmaceutically acceptable salt, tautomer, or solvate thereof;wherein n is 0-2X4, X5, X6, and X7are independently N or CRC;R1, R6, R7, and Rcare the same or different and independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl,C6-C24 aralkyl, halo, -Si(Ci-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanate, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinate, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6and R7may be linked to form a cyclic or polycyclic ring, wherein thering is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl;U1is N, C-R2, or C-NR3R4, wherein R2is selected from the group consisting of a H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, O-CH2-CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=0)N(R')2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1and R2may be linked to form a cyclic or polycyclic ring, wherein R3and R4are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R')2, COOR’ (wherein R’ is II or a lower alkyl group), and R3or R4may be absent; andZ1is O, S, CRaRbor NRa, wherein Raand Rbare independently H or a C1-8 alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted.

[0114] In yet other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (III) or (IV):pharmaceutically acceptable salt, tautomer, or solvate thereof;wherein n is 0-2X6is independently N or CRC;R1, R6, R7, and Rcare the same or different and independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl,C6-C24 aralkyl, halo, -Si(Ci-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C2-C24 alkylamido substituted with a hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5- C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinate, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6and R7may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl;U1is N, C-R2, or C-NR3R4, wherein R2is selected from the group consisting of a H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, O-CH2- CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=0)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1and R2may be linked to form a cyclic or polycyclic ring, wherein R3and R4are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3or R4may be absent;Z1is O, S, CRaRbor NRa, wherein Raand Rbare independently H or a C1-8 alkyl, which is linear, branched, or cyclic, and which is unsubstituted or substituted.

[0115] In some embodiments, R1is selected from the group consisting of branched,linear, or cyclic alkyl,wherein n2=0-6 and X is any of the following: CFyHz(y + z =

[0116] In other embodiments, R6and R7can each independently be one of the following:R73, and R74are the same or different and are independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O)(Ci-Ce alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-Cs alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO ), carbamoyl (-(C0)-NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(Ci-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(C0)-NH2), cyano(-CN), isocyano (-N+C-), cyanato (-O-CN), isocyanato (-O-N+=C‘), isothiocyanate (-S-CN), azido (-N=N+=N“), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2), C1-C24 alkyl amino, C1-C24 alkyl amino substituted with hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamide (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O ), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(0)(0H)2), phosphonato (-P(O)(O’)2), phosphinate (-P(O)(O‘)), phospho (-PO2), phosphino (-PH2). polyalkyl ethers (-[(CH2)n0]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0117] In still other embodiments, R6and R7can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linkedto a phosphate ester (-OPO3H2), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group.

[0118] In other embodiments, the 15-PGDH inhibitor can include a compound having the following formula (V):pharmaceutically acceptable salt, tautomer, or solvate thereof;wherein n is 0-2X6is independently is N or CRCR1, R6, R7, and Rcare the same or different each independently hydrogen or a substituted or unsubstituted group selected from C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, -Si(Ci-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanate, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C2-C24 alkylamido substituted with a hydroxyl, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinate, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, and wherein R6and R7may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; and U1is N, C-R2, or C-NR3R4, wherein R2is selected from the group consisting of a H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, O-CH2-CH2X, CH2-CH2-CH2X, O-CH2-CH2X, X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R', (C=O)N(R’)2, O(CO)R’, COOR’ (wherein R’ is H or a lower alkyl group), and wherein R1and R2may be linked to form a cyclic or polycyclic ring, wherein R3and R4are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)niOR’ (wherein nl=l, 2, or 3), CF3, CH2-CH2X, CH2-CH2-CH2X, (wherein X=H, F, Cl, Br, or I), CN, (C=O)-R’, (C=O)N(R’)2, COOR’ (wherein R’ is H or a lower alkyl group), and R3or R4may be absent.

[0119] In some embodiments, R1is selected from the group consisting of branched,linear, or cyclic alkyl,wherein n2=0-6 and X is any of the following: CFyHz(y + z =

[0120] In other embodiments, R6and R7can each independently be one of the following:51 52 53 54 55 R56 R57 58 5 J^60 61 R62 R63 64 R65 66 R67 R68 R69 J^70 71 j^72 R73, and R74are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-6 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O)(Ci-Ce alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-Cj alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO ), carbamoyl (-(CO)-NH2), C1-C24 alkyl-carbamoyl (-(CO)-NH(Ci-C24 alkyl)), arylcarbamoyl (-(CO)-NH- aryl), thiocarbamoyl (-(CS)-NH2), carbamido (-NH-(CO)-NH2), cyano(-CN), isocyano (-N+C-), cyanato (-O-CN), isocyanato (-O-N+=C'), isothiocyanate (-S-CN), azido (-N=N+=N“), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH2). C1-C24 alkyl amino, C1-C24 alkyl amino substituted with hydroxyl, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl),C6-C20 arylamido (-NH-(CO)-aryl), sulfanamide (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl. C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O ), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono (-P(0)(0H)2), phosphonato (-P(O)(O )2), phosphinato (-P(O)(O )), phospho (-PO2), phosphino (--PH₂), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-0P(0)(0R)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0121] In still other embodiments, R6and R7can independently be a group that improves aqueous solubility, for example, a phosphate ester (-OPO3H2), a phenyl ring linked to a phosphate ester (-OPO3H2), a phenyl ring substituted with one or more methoxyethoxy groups, or a morpholine, or an aryl or heteroaryl ring substituted with such a group.

[0122] In other embodiments, the 15-PGDII inhibitor can include a compound having a structure of formula (IA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl:R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3;R7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR3-alkyl, each of which is optionally substituted with one or more R4; R3is oxo, -OH, -O-alkylene-OH, -O-alkylene-NIR’, -N(R5)2,-N(R5)(alkylene-OH), -N(R5)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R10; R4is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(O)-alkyl, -C(0)-cycloalkyl, alkyl, -alkylene-O-alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylenearyl optionally substituted with R8;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl;or alternatively, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;R9is H or alkyl, or two R9together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(0)t, or N;R10is -OH, halogen, alkyl, or alkoxy;X is N or CH;m is 0, 1, or 2;n is 0, 1, or 2; andtis 0, 1, or 2.

[0123] In some embodiment, the 15-PGDH inhibitor can include a compound having a structure of formula (IIA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is alkyl, haloalkyl, cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene -heterocyclyl;R2is -NH2. CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3; R7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl,-C(O)O-alkyl, or -C(O)NR:’-alkyl, each of which is optionally substituted with one or more R4;R3is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl;R4is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(0)-alkyl, -C(O)-cycloalkyl, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl;or alternatively, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;R9is H or alkyl, or two R9together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N;X is N or CH;m is 0, 1, or 2;n is 0, 1, or 2; andt is 0, 1, or 2.

[0124] In some embodiments, R1is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 6-mcmbcrcd cycloalkyl, -(Ci-Ce alkylene)-(3- to 6-membered cycloalkyl), -(Ci-Ce alkylene)-(Ci-C6 alkoxy), 3- to 6-membered heterocyclyl, or -(Ci-Ce alkylene)-(3- to 6-membered heterocyclyl).

[0125] In other embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)p-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3.

[0126] In still other embodiments, R2is -NH2.

[0127] In some embodiments, R6is 5- to 6-membered heterocyclyl or 5- to 10-mcmbcrcd hctcroaryl, each of which is optionally substituted with one or more R3.

[0128] In other embodiments, R6is 5- to 6-membered heteroaryl optionally substituted with one or more R3.

[0129] In still other embodiments, Rcis 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3.

[0130] In some embodiments, R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(Ci-C6 alkyl), -C(O)O(Ci-C6 alkyl), or -C(O)NR5(Ci-Ce alkyl), each of which is optionally substituted with one or more R4.

[0131] In other embodiments, R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4.

[0132] In still other embodiments, R7is Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 5- to 10-membered heteroaryl each of which is optionally substituted with one or more R4.

[0133] In some embodiments, R3is -O-(Ci-Ce alkylene)-N(R5)2, -N(R5)2, -N(R5)(CI-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6 alkylene-OH), -C(O)(Ci-Cs alkyl), -C(O)O(Ci-Ce alkyl), or -S(O)m(Ci-C6 alkyl).

[0134] In other embodiments, R3is -(C1-C3 alkyl)OH, -NH2, -N(CI-C3alkyl)2, -NIICII2CII2OII, -N(CI-C3alkyl)CII2CIl2OII, N(CII2CIl2OII)2, -NIICII2CII(CIl2OII)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(Ci-C3alkyl), or -OCH2CH2N(CI-C alkyl)2.

[0135] In other embodiments, R3is -NH2, -N(CI-C3alkyl)2, -NHCH2CH2OH, -N(CI-C3alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(CI-C3alkyl)2.

[0136] In still other embodiments, R3is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0137] In some embodiments, R4is halogen, -CN, -N(R5)2, -OH, -O-(Ci-Ce alkylene)-OH, -S(O)m(Ci-C6alkyl), -C(O)(Ci-C6alkyl), -C(O)-(3- to 6-membered cycloalkyl), Ci-C6alkyl, Ci-C6haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[0138] In some embodiments, n is 1.

[0139] In other embodiments, the compound has the structure of formula (IIIA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is 3- to 6-membered cycloalkyl, -(Ci-Ce alkylene)-(3- to 6-membered cycloalkyl), 3-to 6-mcmbcrcd heterocyclyl, or -(Ci-Ce alkylcnc)-(3- to 6-mcmbcrcd heterocyclyl);R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3;R7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR:’-alkyl, each of which is optionally substituted with one or more R4;R3is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl,R4is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH,-S(O)m-alkyl, -C(O)-alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene-aryl optionally substituted with R8;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl;or alternatively, two R’ together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;R9is H or alkyl, or two R9together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N;X is N or CH;m is 0, 1, or 2; andtis 0, 1, or 2.

[0140] In some embodiments, R1is 3- to 5-membered cycloalkyl or -(Ci-Ce alkylene)-(3- to 5-membered cycloalkyl).

[0141] In other embodiments, R1is cyclobutyl.

[0142] In still other embodiments, R1is a bicyclic 4- to 6-membered cycloalkyl.

[0143] In some embodiments, R7is Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(Ci-Ce alkyl), -C(O)O(Ci-C6 alkyl), or -C(O)NR5(Ci-Ce alkyl), each of which is optionally substituted with one or more R4.

[0144] In other embodiments, R7is C1-C4 alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7is Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4.

[0145] In other embodiments, R7is C1-C3 alkyl, C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7is C1-C3 haloalkyl, 3-mcmbcrcd cycloalkyl, phenyl, 4-mcmbcrcd heterocyclyl, or 5- to 6-mcmbcrcd hctcroaryl, each of which is optionally substituted with one or more R4.

[0146] In other embodiments, R7is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, pyrazole, or tri azole, each of which is optionally substituted with one or more R4. In other embodiments, R7is -CF3, cyclopropyl, phenyl, pyridyl, pyrazole, or triazole, each of which is optionally substituted with one or more R4.

[0147] In some embodiments, R3is -O-(Ci-Ce alkylene)-N(R:’)2, -N(R5)2, -N(R5)(CI-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6alkylene-OH), -C(O)(Ci-C6alkyl), -C(O)O(Ci-C6 alkyl), or -S(O)m(Ci-C6 alkyl).

[0148] In other embodiments, R3is -NH2, -N(CI-C3alkyl)2, -NHCH2CH2OH, -N(CI-C3alkyl)CH2CH2OH, N(CH2CH2OH)2. -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(CI-C3alkyl)2.

[0149] In still other embodiments, R3is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0150] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that substituents at the R7position could be modified to improve hERG activity, including hERG inhibition (IC50), blockade, and efflux ratio. For example, in some embodiments, certain 6- to 10-membered aryls (e.g., optionally substituted phenyl) and 5 -to 10-membered heteroaryls (e.g., optionally substituted pyridyls, pyrazoles, and triazoles) were observed to have beneficial hERG properties. In some embodiments, certain Ci-Ce haloalkyls (e.g., -CF3) exhibited improved hERG inhibition (IC50), while also improving half-life and solubility.

[0151] In other embodiments, the compound has the structure of formula (IVA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl;R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3;R7is Ci-Ce haloalkyl, aryl or heteroaryl, each of which is optionally substituted with one or more R4;R3is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl,-C(O)O-alkyl, or -S(O)m-alkyl;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with-OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)m-alkyl;or alternative, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R4is halogen, alkyl, or alkoxy;X is N or CH; andm is 0, 1, or 2.

[0152] In some embodiments, R7is -CF3, pyridyl, pyrazole, phenyl, or triazole, each of which is optionally substituted with R4.

[0153] In other embodiments, R7is -CF3, pyridyl, fluorophenyl, or a triazole optionally substituted with halogen or methyl.

[0155] In still other embodiments, R7is — CF3.

[0156] In still other embodiments, R7is F

[0158] In some embodiments, R7is

[0159] In other embodiments, R6is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3.

[0160] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that 3- to 6-membered cycloalkyls at the R7position can improve solubility while maintaining PDGH activity.

[0161] In other embodiments, the compound has the structure of formula (VA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl;R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3;R7is 3- to 6-membered cycloalkyl, optionally substituted with one or more R4; R is oxo, -OH, -O-alkylene-N(R5)2. -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl;R4is halogen, -CN, -NH2, -OH, or C1-C3 alkyl;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -alkylene-COOH, -C(O)O-alkyl, or -S(O)m-alkyl;or alternative, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;X is N or CH;m is 0, 1, or 2.

[0162] In some embodiments, R7is cyclopropyl.

[0163] In other embodiments, R1is 3- to 6-membered cycloalkyl, -(Ci-Ce alkylene)-(3-to 6-membered cycloalkyl), -(Ci-Ce alkylene)-(Ci-Ce alkoxy), 3- to 6-membered heterocyclyl, or -(Ci-Ce alkylene)-(3- to 6-membered heterocyclyl).

[0164] In some embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)P-cyclopropyl, -(CH2)P-cyclobutyl, -(CH2)P-cyclopentyl, or -(CH2)P-cyclohexyl; wherein p is 1, 2, or 3.

[0165] In some embodiments, R is -O-(Ci-Ce alkylene)-N(R:’)2, -N(R5)2, -N(R5)(CI-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6alkylene-OH), -C(O)(Ci-C6alkyl), -C(O)O(C1-C6alkyl), or -S(O)m(Ci-C6alkyl).

[0166] In some embodiments, R3is -NIh, -N(CI-C3alkyl)2, -NIICII2CII2OII, -N(CI-C3alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(C1-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(Ci-C3alkyl)2.

[0167] In other embodiments, R3is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0168] In some embodiments and without being limited by theory, Applicants surprisingly and unexpectedly discovered that the R6position can be substituted with certain R3groups to improve solubility and activity.

[0169] In other embodiments, the compound has the structure of formula (VIA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is cycloalkyl, -alkylene-cycloalkyl, -alkylene-alkoxy, heterocyclyl, or -alkylene-heterocyclyl;R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is substituted with one or more R3;R7is haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR5-alkyl, each of which is optionally substituted with one or more R4;R3is -O-(Ci-C6alkylene)-N(R5)2, -N(R5)2, -N(R5)(CI-C6alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6alkylene-OH), -C(O)(Ci-C6alkyl), -C(O)O(Ci-C6alkyl), or -S(O)m(Ci-C6alkyl);R4is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(0)-alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene- aryl optionally substituted with R8;each R5is independently H, Ci-Ce alkyl, -(Ci-Ce alkylene)-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)(Ci-C6alkyl), -C(O)O(Ci-C6alkyl), alkylene-COOH, or -S(O)m(Ci-C6alkyl);or alternative, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;X is N or CH;m is 0, 1, or 2.

[0170] In some embodiments, R is -O-(Ci-C6alkylene)-N(R5)2, -N(R5)2or -N(R5)(CI-Ce alkylene-OH).

[0171] In other embodiments, R5is H, Ci-Ce alkyl, -(Ci-Ce alkylene)-OH, or -S(O)2(Ci-C3alkyl).

[0172] In some embodiments, R is -NH2, -N(CI-C3alkyl)2, -NHCH2CH2OH, -N(CI-C3alkyl)CH2CH2OH. N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(Ci-C3alkyl)2.

[0173] In other embodiments, R3is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0174] In still other embodiments, R3is -NHCH2CH2OH.

[0175] In some embodiments, R6is 5- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R3.

[0176] In other embodiments, R6is 5- to 6-membered heteroaryl optionally substituted with one or more R3.

[0177] In some embodiments, R6is furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isooxazole, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine, each optionally substituted with one or more R3.

[0178] In other embodiments, R6is thiazole, imidazole, oxazole, pyridine, or pyrimidine.

[0179] In some embodiments, R6is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3.

[0180] In other embodiments, R6is 5- to 6-membered heterocyclyl, optionally substituted with one or more R3, selected from morpholine, pyridine-one, or piperidine.

[0181] In some embodiments, R7is C1-C3 haloalkyl, 3-membered cycloalkyl, phenyl, 4-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4.

[0182] In other embodiments, R7is -CF3, cyclopropyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4.

[0183] In some embodiments, the compound has the structure of formula (VII A):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is cycloalkyl, alkylene-cycloalkyl, alkylene-alkoxy, heterocyclyl, or alkylene-heterocyclyl;R2is -NH2, CN, or -NHC(O)alkyl:R6is fused bicyclic heterocyclyl or fused bicyclic heteroaryl, each of which is optionally substituted with one or more R3;R7is alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(O)-alkyl, -C(O)O-alkyl, or -C(O)NR3-alkyl, each of which is optionally substituted with one or more R4;R3is oxo, -OH, -O-alkylene-N(R5)2, -N(R5)2, -N(R5)(alkylene-OH), alkyl, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl;R4is oxo, halogen, -CN, -N(R5)2, -OH, -O-alkylene-OH, -S(O)m-alkyl, -C(0)-alkyl, -C(O)-cycloalkyl, alkyl, haloalkyl, cycloalkyl, heterocyclyl, or -alkylene- aryl optionally substituted with R8;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl;or alternatively, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;X is N or CH; andm is 0, 1, or 2.

[0184] In some embodiments, R6is 8- to 10-membered fused bicyclic heteroaryl, each of which is optionally substituted with one or more R3.

[0185] In some embodiments, R7is Ci-Ce alkyl, Ci-Cs haloalkyl, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -C(O)(Ci-C6alkyl), -C(O)O(Ci-C6alkyl), or -C(O)NR5(CI-C6alkyl), each of which is optionally substituted with one or more R4.

[0186] In other embodiments, R7is C1-C4 alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4. In other embodiments, R7is Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R4.

[0187] In still other embodiments, R7is C1-C3 alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more R4.

[0188] In other embodiments, R7is C1-C3 alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4. In other embodiments, R7is Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl,phenyl, pyrazole, pyridyl, or triazole, each of which is optionally substituted with one or more R4.

[0189] In other embodiments, R7is -CF3, isopropyl, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4. In other embodiments, R7is -CF3, cyclopropyl, phenyl, pyridyl, or triazole, each of which is optionally substituted with one or more R4.

[0190] In some embodiments, R1is Ci-Ce alkyl, Ci-Cs haloalkyl, 3- to 6-membered cycloalkyl, -(Ci-Ce alkylene)-(3- to 6-membered cycloalkyl), -(Ci-Ce alkylene)-(Ci-Ce alkoxy), 3- to 6-membered heterocyclyl, or -(Ci-Ce alkylene)-(3- to 6-membered heterocyclyl).

[0191] In other embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-cyclopropyl, -(CH2)p-cyclobutyl, -(CH2)P-cyclopentyl, or -(CH2)p-cyclohexyl; wherein p is 1, 2, or 3.

[0192] In some embodiments, R3is -O-(Ci-C6alkylene)-N(R5)2, -N(R5)2, -N(R5)(CI-C6alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6alkylene-OH), -C(O)(Ci-C6alkyl), -C(O)O(Ci-C6alkyl), or -S(O)m(Ci-C6alkyl).

[0193] In other embodiments, R3is -NH2, -N(Ci-C3alkyl)2, -NHCH2CH2OH, -N(CI-C3alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(C1-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(Ci-C3alkyl)2.

[0194] In some embodiments, R is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0195] In other embodiments, R4is halogen, -CN, -N(R5)2, -OH, -O-(Ci-Ce alkylene)- OH, -S(O)m(Ci-C6 alkyl), -C(O)(Ci-Ce alkyl), -C(O)-(3- to 6-membered cycloalkyl), Ci-Ce alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[0196] In some embodiments, the compound has the structure of formula (VIIIA):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein:R1is cyclobutyl or -(C1-C4 alkylene)-(Ci-C3 alkoxy);R2is -NH2, CN, or -NHC(O)alkyl;R6is heterocyclyl or heteroaryl, each of which is optionally substituted with one or more R3;R3is oxo, -OH, -O-alkylene-OH, -O-alkylene-N(R5)2, -N(R3)2, -N(R5)(alkylene-OH), -N(R5)(alkylene-O-alkyl), alkyl, -alkylene-OH, haloalkyl, cycloalkyl, heterocyclyl, -C(O)N(R5)2, -C(O)N(R5)(alkylene-OH), -C(O)-alkyl, -C(O)O-alkyl, or -S(O)m-alkyl, wherein the cycloalkyl and the heterocyclyl is each optionally substituted with R10; R4is C1-C3 alkyl;each R5is independently, H, alkyl, -alkylene-OH optionally substituted with -OH, -alkylene-NH2, -alkylene-N(R9)2, -alkylene-O-alkylene-OH, -alkylene-O-alkylene-NH2, -C(O)-alkyl, -C(O)O-alkyl, -alkylene-COOH, or -S(O)m-alkyl;or alternatively, two R5together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S, or N, and wherein the heterocycle is optionally substituted with R8;R8is halogen, alkyl, or alkoxy;R9is H or alkyl, or two R9together with the N atom to which they are attached can form a 4- to 7-membered heterocycle, optionally containing an additional heteroatom selected from O, S(O)t, or N;R10is -OH, halogen, alkyl, or alkoxy;X is N or CH;m is 0, 1, or 2;p is 0 or 1; andt is 0, 1, or 2.

[0197] In still other embodiments, R2is -NH2.

[0198] In some embodiments, R6is 5- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R3.

[0199] In other embodiments, R6is 5- to 6-membered heteroaryl optionally substituted with one or more R3.

[0200] In still other embodiments, R6is 8- to 10-membered bicyclic heteroaryl optionally substituted with one or more R3.

[0201] In some embodiments, R3is -O-(C1-C6alkylene)-N(R5)2, -N(R5)2, -N(R5)(CI-C6 alkylene-OH), -C(O)N(R5)2, -C(O)N(R5)(CI-C6alkylene-OH), -C(O)(Ci-C6alkyl), -C(O)O(C1-C6alkyl), or -S(O)m(Ci-C6alkyl).

[0202] In other embodiments, R3is -(C1-C3 alkyl)OH, -NH2, -N(CI-C3alkyl)2, -NHCH2CH2OH, -N(CI-C3alkyl)CH2CH2OH, N(CH2CH2OH)2, -NHCH2CH(CH2OH)2, -N(CI-C3alkyl)CH2CH(CH2OH)2, -NHCH2CH2OCH2CH2OH, -NHCH2CH2OCH2CH2NH2, -NHCH2CH2NH2, -N(CI-C3alkyl)CH2CH2NH2, -NHCH2CH2NH(CI-C3alkyl), -NHCH2CH2N(CI-C3alkyl)2, -N(CI-C3alkyl)CH2CH2NH(Ci-C3alkyl), -N(CI-C3alkyl)CH2CH2N(Ci-C3alkyl)2, -NHSO2CH3, -N(CI-C3alkyl)SO2CH3, -OCH2CH2OH, -OCH2CH2NH2, -OCH2CH2NH(CI-C3alkyl), or -OCH2CH2N(CI-C3alkyl)2.

[0203] In still other embodiments, R3is -NHCH2CH2OH or -N(CH3)CH2CH2OH.

[0204] In some embodiments, R4is halogen, -CN, -N(R3)2, -OH, -O-(Ci-Cealkylene)-OH, -S(O)m(Ci-C6alkyl), -C(O)(Ci-C6alkyl), -C(O)-(3- to 6-membered cycloalkyl), Ci-C6alkyl, Ci-Ce haloalkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl.

[0205] In some embodiments, n is 1.

[0206] In some embodiments, the compound has the structure of formula (IX A):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R1is cyclobutyl or -(C1-C4 alkylene)-(Ci-C3alkoxy);R2is -NH2, CN, or -NHC(O)alkyl;, each of which is optionally substituted with one or more R3;R7is -CF3, isopropyl, cyclopropyl, cyclobutyl, QH,, or, each of which is optionally substituted with one or more R4;R3is -NH2, -NH(CI-C3alkyl), -NH(CI-C4alkylene)-OH, or C1-C3 alkyl; R4is C1-C3 alkyl; andX is N or CH.

[0207] In some embodiments of Formula (IXA), R1is cyclobutyl. In some embodiments of Formula (IXA), R1-(C1-C4 alkylene)-(Ci-C3 alkoxy). In some embodiments of Formula (IXA), the R1-(C1-C4 alkylene)-(Ci-C3 alkoxy) is -(C2-C3 alkylene)-(Ci alkoxy).

[0208] In some embodiments of Formula (IXA), R2is -NH2.

[0210] In some embodiments of Formula (IXA), R3is -NH2. In some embodiments of Formula (IXA), R3is -NH(Ci-C3alkyl). In some embodiments of Formula (IXA), R3is -NH(CI-C4 alkylene)-OH (e.g., -NH(C2-C4 alkylene)-OH). In some embodiments of Formula (IXA), R3is C1-C3 alkyl (e.g., methyl or ethyl).

[0211] In some embodiments, of Formula (IXA), R7is -CF3, isopropyl, cyclopropyl, or cyclobutyl. In some embodiments, of Formula (IXA), R7is isopropyl. In some embodimentsof Formula (VII), R7is, each of which is optionally substituted with one or more R4. In some embodiments, each R4is independently selected from methyl or ethyl.

[0212] In some embodiments of Formula (IXA), X is -CH.

[0213] Examples of compounds having formulas (I), (II), (III), (IV), (V), (IA), (IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), (VIIIA), and (IXA) are described in U. S. Patent Application Publication Nos. 2015 / 0072998, 2017 / 0165241, 2017 / 0173028, 2018 / 0118756, WO2018 / 218251, and WO2020 / 106998, all of which are incorporated by reference in their entirety.

[0214] In other embodiments, the compound can include at least one of the formulas (IB) or (IIB), or a pharmaceutically acceptable salt thereof:wherein X1is N or CR4;X2is S, S=0, S(=0)2, or C=0;X3is CR8, the compound forming a polycyclic heteroaryl with 10 ring atoms, or absent, the compound forming a polycyclic heteroaryl with 9 ring atoms;X4is N, NH, or CR7;X5is N, C=O, or CR16, and X5is N if X4is CR7, or X3is absent, X4is NH if X5is C=O, and X5is CR16if X4is N and X3is CR8;R1, R2, R3, R4R9, R10, and R16are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O) (Ci-Ce alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-Caalkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy(-COOH), carboxylate (-COO ), carbamoyl (-(COf-NFh), C1-C24 alkyl-carbamoyl(-(CO)-NH(CI-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(C0)-NH2), cyano(-CN), isocyano (-N+C_), cyanate (-O-CN), isocyanate (-O-N+=C-), isothiocyanate (-S-CN), azido (-N=N+=N-), formyl (-(CO)-H), thioformyl (-(CS)-II), amino (-NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonate (-SO2-O ), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently II, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinate (-P(O)(O-)), phospho (-PO2), phosphino (-PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof;R7and R8are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R7or R8is not H; andwherein the compound is not

[0215] In some embodiments, at least one of R2or R3is not H, and at least one of R9or R10is not H.

[0216] In some embodiments, the 15-PGDH inhibitor can include a compound having at least one of the following formulas:pharmaceutically acceptable salt thereof;wherein X2is S, S=O, S(=O)2, or C=O;X6is Cl, Br, or F, and y + z = 3;R1, R2, R3, R5, R6, and R14are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl,C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O) (Ci-Ce alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-C_ alkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO ), carbamoyl (-(C0)--NIl2), C1-C24 alkyl-carbamoyl(-(CO)-NH(CI-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl(-(CS)-NH2), carbamide (-NH-(C0)-NH2), cyano(-CN), isocyano (-N+C), cyanato (-O-CN), isocyanato (-O-N+=C-), isothiocyanate (-S-CN), azido (-N=N+=N-), formyl (-(CO)— H), thioformyl (-(CS)-H), amino (-NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamido (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonato (-SO2-O-), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently H, aryl or alkyl), phosphono(-P(O)(OH)2), phosphonato (-P(O)(O )2), phosphinate (-P(O)(O )), phospho (-PO2), phosphino (-PH2), polyalkyl ethers (-[(CH2)n0]m), phosphates, phosphate esters[-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof; wherein R5and R6may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, n1is 0-4, and each R14is the same or different.

[0217] In other embodiments, the 15-PGDH inhibitor can include a compound having at least one of the following formulas:pharmaceutically acceptable salt thereof;wherein X7is S, S=O, S(=O)2, or C=O;R7and R8are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R7or R8is not H;R9, R10, R11, R12, R13, and R15are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, (wherein from 1-3 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O) (Ci-Ce alkyl), O, and S), heteroaryl or heterocyclyl containing from 5-14 ring atoms, (wherein from 1-6 of the ring atoms is independently selected from N, NH, N(Ci-Calkyl), O, and S), C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl (including C2-C24 alkylcarbonyl (-CO-alkyl) and C6-C20 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C24 alkoxycarbonyl (-(CO)-O-alkyl), C6-C20 aryloxycarbonyl (-(CO)-O-aryl), C2-C24 alkylcarbonato (-O-(CO)-O-alkyl), C6-C20 arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylate (-COO ), carbamoyl (-(COf-NFh), C1-C24 alkyl-carbamoyl(-(CO)-NH(CI-C24 alkyl)), arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(C0)-NH2), cyano(-CN), isocyano (-N+C_), cyanate (-O-CN), isocyanate (-O-N+=C-), isothiocyanate (-S-CN), azido (-N=N+=N-), formyl (-(CO)-H), thioformyl (-(CS)-II), amino (-NH2), C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido (-NH-(CO)-alkyl), C6-C20 arylamido (-NH-(CO)-aryl), sulfanamide (-SO2N(R)2 where R is independently H, alkyl, aryl or heteroaryl), imino (-CR=NH where R is hydrogen, C1-C24 alkyl, C5-C20 aryl, C6-C24 alkaryl, C6-C24 aralkyl, etc.), alkylimino (-CR=N(alkyl), where R=hydrogen, alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-NO2), nitroso (-NO), sulfo (-SO2-OH), sulfonate (-SO2-O ), C1-C24 alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), C1-C24 alkylsulfinyl (-(SO)-alkyl), C5-C20 arylsulfinyl (-(SO)-aryl), C1-C24 alkylsulfonyl (-SO2-alkyl), C5-C20 arylsulfonyl (-SO2-aryl), sulfonamide (-SO2-NH2, -SO2NY2 (wherein Y is independently II, aryl or alkyl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinate (-P(O)(O-)), phospho (-PO2), phosphino (-PH2), polyalkyl ethers (-[(CH2)nO]m), phosphates, phosphate esters [-OP(O)(OR)2 where R = H, methyl or other alkyl], groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, and combinations thereof; wherein R12and R13may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, n2is 0-4, and each R15is the same or different.

[0218] Still other examples of 15-PGDH inhibitors include compounds described in W02022 / 032230A1, WO2021 / 236779A1, W02020 / 106998A1, WO2018 / 218251A1, W02018 / 145080A1, WO2016 / 168472A1, WO2015 / 065716A1, WO2013 / 158649A1, WO2024 / 233550A1, U. S. Patent Application Publication No. 2024 / 0294519A1, U. S. PatentApplication Publication No. 2024 / 0374579A1, and U. S. Patent Application Publication No.2024 / 0409557 all of which are herein incorporated by reference in its entirety.

[0219] For example, the 15-PGDH inhibitor can be a 5,6-fused and 6,6-fused bicyclic alcohol or ether described in U. S. Patent Application Publication No. 2024 / 0409557. A 5,6-fused and 6,6-fused bicyclic alcohol or ether can be a compound of Formula (A):or pharmaceutically acceptable salts thereof;whereinm is 0 or 1;X is N or CH; Y is N or CR3;Z is N or CR5;b is N or CR4;Rlais H, deuterium, Ci-6 alkyl, or Ci-6 haloalkyl;wherein, when Rlais Ci-6 alkyl or Ci-6 haloalkyl, then Rlamay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rfc)2, C1-3 alkyl, or C1-3 alkoxy;R1bis -H, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -(C1-6 alkylene)-O-( C1-6 alkyl), C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members; wherein, when R1bis C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -(C1-6 alkylene)-O-( C1-6 alkyl), C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members, then R1bmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rb)2, C1-3 alkyl, or C1-3 alkoxy; wherein each of the C1-3 alkyl and C1-3 alkoxy may be unsubstituted or substituted with 1 to 6 F groups;or, alternatively, R1aand R1btogether form a C3-10 cycloalkyl, C3-10 cycloalkenyl, or heterocyclyl having 3 to 10 ring members;wherein the R1aand R1bcycle may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-3 alkyl, C1-3 alkoxy, -CN, C1-6 heteroalkyl, C3-10 cycloalkyl, or heterocyclyl having 3 to 10 ring members; wherein each of the C1-3 alkyl and C1-3 alkoxy may be unsubstituted or substituted with 1 to 9 halogen groups or C1-3 alkoxy;R1cis -H, C1-6 alkyl, or C3-6 cycloalkyl; wherein, when R1cis C1-6 alkyl or C3-6 cycloalkyl, then R1cmay be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, -N(Rb)2, C1-3 alkyl, C1-3 alkoxy, or C1-6 heteroalkyl; R2is C3-20 cycloalkyl, C3-20 cycloalkenyl, C6-18 aryl, heteroaryl having 5 to 20 ring members, or heterocyclyl having 3 to 20 ring members; wherein R2may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylene-OH, C1-6 alkylene-O- C1-6 alkyl, or C1-6 heteroalkyl;R3is -H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, amino, C1-4 alkyl-amino, di-C1-4 alkyl-amino, C6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members; wherein, when R3is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-4 alkyl-amino, di-C1-4 alkyl-amino, C6-10 aryl, heteroaryl having 5 to 10 ring members, or heterocyclyl having 5 to 10 ring members, then R3may be unsubstituted or substituted with one or more substituents, each of which independently is halogen, -OH, oxo, -N(Rb)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkylene-Ci-3 alkoxy, Ci-6 heteroalkyl, or two R3substituents together form a C3-6 carbocyclyl or a heterocyclyl having 3 to 6 ring members: R4is -H, C1-3 alkyl, C1-3 haloalkyl, -CN, halogen, or -N(Ra)2 where each instance of Ra, where present, independently is -H, C1-6 alkyl, or -C(O) C1-6 alkyl; or, alternatively, two Rasubstituents together form a heterocyclyl having 3 to 6 ring members;wherein Ramay be unsubstituted or substituted with one or more substituents, each of which independently is -F, -Cl, -OH, C1-3 alkoxy;R5is — H, CM alkyl, C3-6 cycloalkyl, Ci-6 haloalkyl, or Ci-6 heteroalkyl; wherein, when R’ is C1-6 alkyl, C3-6 cycloalkyl, CM haloalkyl, or C hctcroalkyl, then R may be unsubstituted or substituted one or more substituents, each of which independently is halogen, -OH, C1-3 alkyl, or C1-3 alkoxy;where each instance of Rb, where present, independently is -H or C1-6 alkyl; or, alternatively, two Rbsubstituents together form a heterocyclyl having 3 to 6 ring members; andwherein, when Rbis C1-6 alkyl or, alternatively, two Rbsubstituents together form a heterocyclyl having 3 to 6 ring members, then Rbmay be unsubstituted or substituted with one or more substituents, each of which independently is -F, -Cl, -OH, C1-3 alkoxy.

[0220] In certain embodiments, the small molecule 15-PGDH inhibitor can be selected that can ia) at 2.5 pM concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70 (using a scale on which a value of 100 indicates a doubling of reporter output over baseline); iia) at 2.5 pM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 75; iiia) at 7.5 M concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion construct to a luciferase output level of greater than 70; and iva) at 7.5 pM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a level greater than 20; and va) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC50 of less than 1 pM.

[0221] In other embodiments, the small molecule 15-PGDH inhibitor can ib) at 2.5 pM concentration, stimulate a Vaco503 reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iib) at 2.5 pM concentration stimulate a V9m reporter cell line expressing a 15-PGDH luciferase fusion construct to increase luciferase output; iiib) at 7.5 pM concentration stimulate a LS174T reporter cell line expressing a 15-PGDH luciferase fusion constmct to increase luciferase output; ivb) at 7.5 pM concentration, does not activate a negative control V9m cell line expressing TK-renilla luciferase reporter to a luciferase level greater than 20% above background; and vb) inhibits the enzymatic activity of recombinant 15-PGDH protein at an IC50 of less than 1 pM.

[0222] In other embodiments, the small molecule 15-PGDH inhibitor can inhibit the enzymatic activity of recombinant 15-PGDH at an IC50 of less than 1 pM, or preferably at an IC50 of less than 250 nM, or more preferably at an IC50 of less than 50 nM, or more preferably at an IC50 of less than 10 nM, or more preferably at an IC50of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.

[0223] It will be appreciated that other 15-PGDH inhibitors can be used in the methods described herein. These other 15-PGDH inhibitors can include known 15-PGDH inhibitors including, for example, tetrazole compounds of formulas (I) and (II), 2-alkylideneaminooxyacetamide compounds of formula (I), heterocyclic compounds of formulas (VI) and (VII), and pyrazole compounds of formula (III) described in U. S. Patent Application Publication No. 2006 / 0034786 and U. S. Patent No. 7,705,041; benzylidene-1,3-thiazolidine compounds of formula (I) described in U. S. Patent Application PublicationNo. 2007 / 0071699; phenylfurylmethylthiazolidine-2, 4-dione and phenylthienylmethylthiazolidine-2, 4-dione compounds described in U. S. Patent Application Publication No. 2007 / 0078175; thiazolidenedione derivatives described in U. S. Patent Application Publication No. 2011 / 0269954; phenylfuran, phenylthiophene, or phenylpyrrazole compounds described in U. S. Patent No. 7,294,641, 5-(3,5-disubstituted phenylazo)-2-hydroxybenzene-acetic acids and salts and lactones described in U. S. Patent No. 4,725,676, and azo compounds described in U. S. Patent No. 4,889,846.

[0224] Still other examples of 15-PGDH inhibitors are described in the following publications: Seo SY et al. Effect of 15 -hydroxyprostaglandin dehydrogenase inhibitor on wound healing. Prostaglandins Leukot Essent Fatty Acids. 2015;97:35-41. doi:10.1016 / j.plefa.2015.03.005. PubMed PMID: 25899574; Piao YL et al. Wound healing effects of new 15 -hydroxyprostaglandin dehydrogenase inhibitors. Prostaglandins Leukot Essent Fatty Acids. 2014;91(6):325-32. doi: 10.1016 / j.plefa.2014.09.011. PubMed PMID: 25458900; Choi D et al. Control of the intracellular levels of prostaglandin E(2) through inhibition of the 15-hydroxyprostaglandin dehydrogenase for wound healing. Bioorg Med Chem. 2013;21(15):4477-84. doi: 10.1016 / j.bmc.2013.05.049. PubMed PMID: 23791868; Wu Y et al. Synthesis and biological evaluation of novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem. 2011;54(14):5260-4. Epub 2011 / 06 / 10. doi: 10.1021 / jm200390u. PubMed PMID: 21650226; Duveau DY et al.Structure-activity relationship studies and biological characterization of human NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors. Bioorg Med Chem Lett. 2014;24(2):630-5. doi: 10.1016 / j.bmcl.2013.11.081. PubMed PMID: 24360556; PMCID: PMC3970110; Duveau DY et al. Discovery of two small molecule inhibitors, ML387 and ML388, of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD)2010; Wu Y et al. Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors. Bioorg Med Chem. 2010;18(4):1428-33. doi: 10.1016 / j.bmc.2010.01.016. PubMed PMID: 20122835; Wu Y et al. Synthesis and biological evaluation of novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase inhibitors. J Med Chem. 2011;54(14):5260-4. Epub 2011 / 06 / 10. doi: 10.1021 / jm200390u. PubMed PMID: 21650226; Jadhav A et al. Potent and selective inhibitors of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD). Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD)2010; Niesen FHet al. High-affinity inhibitors of human NAD-dependent 15-hydroxyprostaglandin dehydrogenase: mechanisms of inhibition and structure-activity relationships. PLoS One. 2010:5(1 l):el3719. Epub 2010 / 11 / 13. doi: 10.1371 / journal.pone.0013719. PubMed PMID: 21072165; PMCID: 2970562; Michelet, J. et al. Composition comprising at least one 15-PGDH inhibitor. US20080206320 Al, 2008; and Rozot, R et al. Care / makeup compositions comprising a 2-alkylideneaminooxyacetamide compound for stimulating the growth of the hair or eyelashes and / or slowing loss thereof. US7396525 B2, 2008.Inhibitory Nucleic Acids

[0225] In other embodiments, a 15-PGDH inhibitor used to treat inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include an inhibitory nucleic acid, e.g., antisense DNA or RNA, morpholino oligomer, small interfering RNA (siRNA), microRNA (miRNA), or short hairpin RNA (shRNA). In some embodiments, the inhibitory RNA targets a sequence that is identical or substantially identical (e.g., at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical) to a target sequence in a 15-PGDH polynucleotide (e.g., a portion comprising at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 contiguous nucleotides, e.g., from 20-500, 20-250, 20-100, 50-500, or 50-250 contiguous nucleotides of a 15-PGDH-encoding polynucleotide sequence (e.g., the human HPGD gene, Gene ID: 3248, including of any of its transcript variants, e.g., as set forth in GenBank Accession Nos. NM_000860.6, NM_001145816.2, NM_001256301.1, NM_001256305.1. NM_001256306.1, NM_001256307.1, or NM_001363574.1).

[0226] In some embodiments, the methods described herein comprise treating a subject with inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages using an shRNA or siRNA. A shRNA is an artificial RNA molecule with a hairpin turn that can be used to silence target gene expression via the siRNA it produces in cells. See, e.g., Fire et.al., Nature 391:806-811, 1998: Elbashir et al., Nature 411:494-498, 2001; Chakraborty etal., Mol Ther Nucleic Acids 8:132-143, 2017; and Bouard et al., Br. J. Pharmacol. 157:153-165, 2009. In some embodiments, a method of treating a subject, e.g., a subject with inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages, comprises administering to the subject a therapeutically effective amount of a modified RNA or a vector comprising a polynucleotide that encodes an shRNA or siRNA capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of the human 15-PGDH-encoding polynucleotide sequence set forth in any of GenBank Accession Nos. NM_000860.6. NM_001145816.2, NM_001256301.1, NM_001256305.1, NM_001256306.1, NM_001256307.1, or NM_001363574.1). In some embodiments, the vector further comprises appropriate expression control elements known in the art, including, e.g., promoters (e.g., inducible promoters or tissue specific promoters), enhancers, and transcription terminators.

[0227] In some embodiments, the 15-PGDH inhibitor is a 15-PGDH-specific microRNA (miRNA or miR). A microRNA is a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs base pair with complementary sequences within the mRNA transcript. As a result, the mRNA transcript may be silenced by one or more of the mechanisms, such as cleavage of the mRNA strand, destabilization of the mRNA through shortening of its poly(A) tail, and decrease in the translation efficiency of the mRNA transcript into proteins by ribosomes.

[0228] In some embodiments, the 15-PGDH inhibitor may be a morpholino oligomer, an antisense oligonucleotide, e.g., an RNase H-dependent antisense oligonucleotide (ASO), or combinations thereof. ASOs are single-stranded, chemically modified oligonucleotides that bind to complementary sequences in target mRNAs and reduce gene expression both by RNase H-mediated cleavage of the target RNA and by inhibition of translation by steric blockade of ribosomes. In some embodiments, the oligonucleotide is capable of hybridizing to a portion of a 15-PGDH mRNA (e.g., a portion of a human 15-PGDH-encoding polynucleotide sequence as set forth in any of GenBank Accession Nos. NM_000860.6, NM_001145816.2, NM_001256301.1, NM_001256305.1, NM_001256306.1,NM_001256307.1, or NM_001363574.1). In some embodiments, the oligonucleotide has a length of about 10-30 nucleotides (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30 nucleotides). In some embodiments, the oligonucleotide has 100% complementarity to theportion of the mRNA transcript it binds. In other embodiments, the DNA oligonucleotide has less than 100% complementarity (e.g., about 95%, about 90%, about 85%, about 80%, about 75%, or about 70% complementarity) to the portion of the mRNA transcript it binds, but can still form a stable RNA: DNA duplex for the RNase H to cleave the mRNA transcript.

[0229] Suitable antisense molecules, siRNA, miRNA, and shRNA can be produced by standard methods of oligonucleotide synthesis or by ordering such molecules from a contract research organization or supplier by providing the polynucleotide sequence being targeted. The manufacture and deployment of such antisense molecules in general terms may be accomplished using standard techniques described in contemporary reference texts: for example, Gene and Cell Therapy: Therapeutic Mechanisms and Strategies. 4thedition by N. S. Templeton; Translating Gene Therapy to the Clinic: Techniques andApproaches, 1.sup.st edition by J. Laurence and M. Franklin; High-Throughput RNAi Screening: Methods and Protocols (Methods in Molecular Biology) by D. O. Azorsa and S. Arora; and Oligonucleotide-Based Drugs and Therapeutics: Preclincal and Clinical Considerations by N. Ferrari and R. Segui.

[0230] Inhibitory nucleic acids can also include morpholino oligomers (DNA bases attached to a backbone of methylenemorpholine rings linked through phosphordiamidate groups), which block access to short (approximately 25 bases) specific sequences of the basepairing surfaces of ribonucleic acid and are used to knock down gene function. Also included are RNA aptamers, which are short, synthetic oligonucleotide sequences that bind to proteins (see, e.g., Li et al., Nuc. Acids Res. (2006), 34:6416-24). Both are notable for both high affinity and specificity for the targeted molecule, and have the additional advantage of being smaller than antibodies (usually less than 6 kD). RNA aptamers with a desired specificity are generally selected from a combinatorial library, and can be modified to reduce vulnerability to ribonucleases, using methods known in the art.Antibodies

[0231] In other embodiments, a 15-PGDH inhibitor used to treat inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include an anti-15-PGDH antibody or an antigenbinding fragment thereof. In some embodiments, the antibody is a blocking antibody (e.g., an antibody that binds to a target and directly interferes with the target’s function,e.g., 15-PGDH enzyme activity). In some embodiments, the antibody is a neutralizing antibody (e.g., an antibody that binds to a target and negates the downstream cellular effects of the target). In some embodiments, the antibody binds to human 15-PGDH.

[0232] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is an antigen-binding fragment, such as a F(ab')2, Fab', Fab, scFv, and the like. The term “antibody or antigen-binding fragment” can also encompass multi-specific and hybrid antibodies, with dual or multiple antigen or epitope specificities.

[0233] In some embodiments, an anti- 15-PGDH antibody comprises a heavy chain sequence or a portion thereof, and / or a light chain sequence or a portion thereof, of an antibody sequence disclosed herein. In some embodiments, an anti- 15-PGDH antibody comprises one or more complementarity determining regions (CDRs) of an anti- 15-PGDH antibody as disclosed herein. In some embodiments, an anti- 15-PGDH antibody is a nanobody, or single-domain antibody (sdAb), comprising a single monomeric variable antibody domain, e.g., a single VHH domain.

[0234] For preparing an antibody that binds to 15-PGDH, many techniques known in the art can be used. See, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983): Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd cd. 1986)). In some embodiments, antibodies are prepared by immunizing an animal or animals (such as mice, rabbits, or rats) with an antigen for the induction of an antibody response. In some embodiments, the antigen is administered in conjugation with an adjuvant (e.g., Freund's adjuvant). In some embodiments, after the initial immunization, one or more subsequent booster injections of the antigen can be administered to improve antibody production. Following immunization, antigen-specific B cells are harvested, e.g., from the spleen and / or lymphoid tissue. For generating monoclonal antibodies, the B cells are fused with myeloma cells, which are subsequently screened for antigen specificity.

[0235] The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Additionally, phage or yeast display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992); Lou et al. in PEDS 23:311 (2010); and Chao et al., Nature Protocols, 1:755-768 (2006)). Alternatively, antibodies and antibody sequences may be isolated and / or identified using a yeast-based antibody presentation system, such as that disclosed in, e.g., Xu et al., Protein Eng Des Sel, 2013, 26:663-670; WO 2009 / 036379; WO 2010 / 105256; and WO 2012 / 009568.Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U. S. Pat. Nos. 4,946,778, 4,816,567) can also be adapted to produce antibodies.

[0236] Antibodies can be produced using any number of expression systems, including prokaryotic and eukaryotic expression systems. In some embodiments, the expression system is a mammalian cell, such as a hybridoma, or a CHO cell. Many such systems are widely available from commercial suppliers. In embodiments in which an antibody comprises both a VH and VL region, the VH and VL regions may be expressed using a single vector, e.g., in a di-cistronic expression unit, or be under the control of different promoters. In other embodiments, the VH and VL region may be expressed using separate vectors.

[0237] In some embodiments, an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and / or light chain sequences that are affinity matured. For chimeric antibodies, methods of making chimeric antibodies are known in the art. For example, chimeric antibodies can be made in which the antigen binding region (heavy chain variable region and light chain variable region) from one species, such as a mouse, is fused to the effector region (constant domain) of another species, such as a human. As another example, “class switched” chimeric antibodies can be made in which the effector region of an antibody is substituted with an effector region of a different immunoglobulin class or subclass.

[0238] In some embodiments, an anti-15-PGDH antibody comprises one or more CDR, heavy chain, and / or light chain sequences that are humanized. For humanized antibodies,methods of making humanized antibodies are known in the art. See, e.g., U. S. Pat. No. 8,095,890. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. As an alternative to humanization, human antibodies can be generated. As a non-limiting example, transgenic animals (e.g., mice) can be produced that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array in such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993):Jakobovits et al., Nature, 362:255-258 (1993); Bruggermann et al., Year in Immun., 7:33 (1993); and U. S. Pat. Nos. 5,591,669, 5,589,369, and 5,545,807.

[0239] In some embodiments, antibody fragments (such as a Fab, a Fab', a F(ab')2, a scFv, nanobody, or a diabody) are generated. Various techniques have been developed for the production of antibody fragments, such as proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem. Biophys. Meth., 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)) and the use of recombinant host cells to produce the fragments. For example, antibody fragments can be isolated from antibody phage libraries. Alternatively, Fab'-SH fragments can be directly recovered from E. coli cells and chemically coupled to form F(ab')2 fragments (see, e.g.. Carter et al., BioTechnology, 10:163-167 (1992)).According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to those skilled in the art.

[0240] Methods for measuring binding affinity and binding kinetics are known in the art. These methods include, but are not limited to, solid-phase binding assays (e.g., ELISA assay), immunoprecipitation, surface plasmon resonance (e.g., Biacore™ (GE Healthcare, Piscataway, NJ)), kinetic exclusion assays (e.g., KinExA®), flow cytometry, fluorescence-activated cell sorting (FACS), BioLayer interferometry (e.g., Octet™ (FortdBio, Inc., Menlo Park, CA)), and western blot analysis.Gene Editing

[0241] In other embodiments, a 15-PGDH inhibitor used to treat inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can include nucleic acid molecules to inhibit 15-PGDH synthesis. The nucleic acid molecules may be used in a TALEN (transcription activator-like effector nuclease technology), zinc-finger nuclease or CRISPR-Cas system to target a nucleic acid sequence for genetic screening, targeted transcriptional regulation, targeted knock-in, and targeted genome editing, including base editing, epigenetic editing, and introducing double strand breaks (DSBs) for homologous recombination-mediated insertion of a nucleotide sequence. Genome editing can refer to the targeted modification of a DNA sequence, including but not limited to, adding, removing, replacing, or modifying existing DNA sequences, and inducing chromosomal rearrangements or modifying transcription regulation elements (e.g., methylation / demethylation of a promoter sequence of a gene) to alter gene expression. In some embodiments, inhibiting 15-PGDH expression comprises inserting a silencer sequence near a polynucleotide sequence encoding 15-PGDH. In yet other embodiments, upregulating PGE2 synthesis comprises inserting an enhancer sequence near a polynucleotide sequence encoding PGE2.

[0242] CRISPR-Cas systems require a guide system that can locate Cas protein to the target DNA site in the genome. In some instances, the guide system comprises a crispr RNA (crRNA) with a 17-20 nucleotide sequence that is complementary to a target DNA site and a trans-activating crRNA (tracrRNA) scaffold recognized by the Cas protein (e.g., Cas9). The 17-20 nucleotide sequence complementary to a target DNA site is referred to as a spacer while the 17-20 nucleotide target DNA sequence is referred to a protospacer. While crRNAs and tracrRNAs exist as two separate RNA molecules in nature, single guide RNA (sgRNA or gRNA) can be engineered to combine and fuse crRNA and tracrRNA elements into one single RNA molecule. Thus, in one embodiment, the CRISPR guide system comprises two or more RNAs, e.g., crRNA and tracrRNA. In another embodiment, the CRISPR guide system comprises a sgRNA comprising a spacer sequence for genomic targeting and a scaffold sequence for Cas protein binding. In some instances, the guide system naturally comprises a sgRNA. For example, Casl2a / Cpfl utilizes a guide system lacking tracrRNA and comprising only a crRNA containing a spacer sequence and a scaffold for Casl2a / Cpflbinding. While the spacer sequence can be varied depending on a target site in the genome, the scaffold sequence for Cas protein binding can be identical for all gRNAs.

[0243] CRISPR-Cas systems described herein can comprise different CRISPR enzymes. For example, the CRISPR-Cas system can comprise Cas9, Casl2a / Cpfl, Casl2b / C2cl, Casl2c / C2c3, Casl2d / CasY, Casl2e / CasX, Cas 12g, Casl2h, or Casl2i. Nonlimiting examples of Cas enzymes include, but are not limited to, Casl, CasiB, Cas2, Cas3, Cas4, Cas5, Cas5d, Cas5t, Cas5h, Cas5a, Cas6, Cas7, Cas8, Cas8a, Cas8b, Cas8c, Cas9 (also known as Csnl or Csxl2), CaslO, CaslOd, Casl2a / Cpfl, Casl2b / C2cl, Casl2c / C2c3, Casl2d / CasY, Casl2e / CasX, Casl2f / Casl4 / C2cl0, Casl2g, Casl2h, Casl2i, Casl2k / C2c5, Casl3a / C2c2, Casl3b, Casl3c, Casl3d, C2c4, C2c8, C2c9, Csyl, Csy2, Csy3, Csy4, Csel, Cse2, Cse3, Cse4, Cse5e, Cscl, Csc2, Csa5, Csnl, Csn2, Csml, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, CsxlS, Csxll, Csfl, Csf2, CsO, Csf4. Csdl, Csd2, Cstl, Cst2, Cshl, Csh2, Csal, Csa2, Csa3, Csa4, Csa5, GSU0054, Type II Cas effector proteins, Type V Cas effector proteins, Type VI Cas effector proteins, CARF, DinG, homologues thereof, or modified or engineered versions thereof such as dCas9 (endonuclease-dead Cas9) and nCas9 (Cas9 nickase that has inactive DNA cleavage domain). In some cases, the compositions, methods, devices, and systems, described herein, may use the Cas9 nucleasefrom Streptococcus pyogenes, of which amino acid sequences and structures are well known to those skilled in the art.

[0244] Binding of a Cas protein to its target DNA sequence (i.e. target dsDNA) requires the presence of a protospacer adjacent motif (PAM), i.e., a short sequence adjacent to the protospacer, on the non-targeted DNA strand, which limits the region in the genome that can be targeted by Cas proteins. Cas proteins from different bacterial species recognize different PAM sequences and make cuts 3-4 nucleotides upstream (e.g., Cas9) or 18-23 nucleotides downstream (e.g., Casl2a / Cpfl) of the PAM sequence. For example, Cas9from Streptococcus pyogene recognizes the PAM sequence 5'-NGG-3' (wherein “N” can be any nucleotide) and cleaves 3 nucleotide upstream of the PAM sequence. In another example, Cas9 from Staphylococcus aureus recognizes the PAM sequence 5'-NNGRRN-3’ (wherein “N” can be any nucleotide) and cleaves 4 nucleotide upstream of the PAM sequence. Although the PAM sequence is essential for Cas-mediated cleavage, in some instances, the gRNA sequence does not comprise a PAM sequence.

[0245] In some embodiments, the nucleic acid molecules can include a target sequence comprising a spacer that is complementary to a sequence at a target site in the genome. A spacer, as described herein, can comprise about 10 to about 25 nucleotides in length. For example, a spacer sequence that is complementary to a target site sequence in the genome can be about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 27, 28, 30, or more nucleotides in length. A target site, as described herein, can comprise a sequence of about 20 nucleotides immediately upstream or 5' of the first nucleotide of the PAM. Provided herein are guide system nucleic acid molecules, wherein at least 1, at least 2, or at least 3 consecutive nucleotides at the 5' terminus of the guide system nucleic acid molecules are 100% identical to the 3' terminus of the target sequence in a genome. Guide system nucleic acid molecules synthesized by the compositions, methods, devises, and systems, described herein, exhibit improved or enhanced pairing with a target sequence via complementary base pairing with the target sequence in a target gene compared to a guide system nucleic acid molecule comprising additional 5' terminal G nucleotide that is not present in the protospacer sequence or complementary to the 3' terminus of the target sequence.

[0246] Guide system nucleic acid molecules can exhibit enhanced editing efficiency of a target sequence when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR-Cas9, CRISPR-Casl2a / Cpfl, etc.). For example, gRNA (guide RNA) provided herein can exhibit enhanced editing efficiency of a target sequence when in complex with a CRISPR-Cas system compared to a gRNA comprising additional one or more 5' terminal G nucleotides, wherein the additional one or more 5' terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3' terminus of the target sequence in a genome. As used herein, the term “codon” generally refers to three consecutive nucleotides, which may or may not encode an amino acid. As used herein, the efficiency of editing” or “editing efficiency” can refer to the ability of a guide system nucleic acid molecule directed effector protein (e.g., CRISPR-Cas protein) to modify a target DNA sequence. Non-limiting examples of modification of a target sequence can include introducing a double stranded break, modifying a nucleobase, inducing chromosomal rearrangements, and modifying methylation / demethylation of a promoter sequence of a gene. A target sequence may be located in a gene or in a promoter region in a genome. An effector protein may be a gRNA directed nuclease, e.g., Cas protein such as Cas9 or any other Casprotein described herein. The editing efficiency can be measured by using any methods well known to one skilled in the art. For example, the efficiency of genome editing or editing efficiency can be measured by using tracking of indels by decomposition ( TIDE) analysis, surveyor nuclease assay, junction PCR, droplet digital PCR (ddPCR), denaturing high-performance liquid chromatography (DHPLC), PCR single-stranded conformational polymorphism (SSCP), high-resolution melting (HRM), restriction enzyme digestion-suppressed PCR (RE-PCR), engineered nuclease-induced translocations (ENIT), restriction enzyme digestion, Sanger DNA sequencing, deep sequencing such as next generation sequencing (NGS), or any combination thereof. The term “indel(s)”, as used herein, refers to the insertion or deletion of a nucleotide base within a nucleic acid. In some embodiments, the efficiency of genome editing, e.g., generating a double-strand break, can be measured by TIDE analysis, a three-step method whereby the region targeted by the nuclease (e.g., Cas9) is PCR-amplified from DNA isolated from cells transfected with CRISPR-Cas system and gRNAs. Amplicons of 500-1500 bp generated around the target site are subject to conventional Sanger DNA sequencing followed by analysis using the web-based TIDE software. Any sequence modifications made by the nuclease are visualized in a graph of the sequence with the aberrant base signal. The software also provides precise localization of break sites and estimated statistical significance of each indel. In some embodiments, the editing efficiency e.g., the efficiency of generating a DNA break in the intended target site, is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0247] In some embodiments, guide system nucleic acid molecules can exhibit reduced off-target editing (e.g., editing of a non-target sequence) when guide system nucleic acid molecules are contacted with the target sequence in a complex with a CRISPR-Cas system (e.g., CRISPR-Cas9, CRISPR-Cas 12a / Cpfl, etc.). For example, gRNA provided herein can exhibit reduced off-target editing when in complex with a CRISPR-Cas system compared to a gRNA comprising additional one or more 5' terminal G nucleotides, wherein the additional one or more 5' terminal G nucleotides are not present in the protospacer sequence or not complementary to one or more nucleotides at the 3' terminus of the target sequence in a genome. In some embodiments, the off-target editing can be reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.Protein Level Control

[0248] In other embodiments, a 15-PGDH inhibitor used to treat inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages can provide regulated degradation of 15-PGDH by incorporating a degron into the amino acid sequence of 15-PGDH that allows recruitment to the endogenous protein turnover machinery. Mechanisms for targeted protein degradation include, but are not limited to, recruitment to an E3 ligase for ubiquitination and subsequent proteasomal degradation, direct recruitment to the proteasome, and recruitment to the lysosome.

[0249] Fusion of inducible degron motifs to 15-PGDH enables exogenous control over the stability of the molecule through the addition or removal of small molecules that stabilize or destabilize the degron, and thus 15-PGDH.

[0250] In some embodiments, methods for inducible protein degradation by a degron includes, but is not limited to, ligand induced degradation (LID) using a SMASH tag, ligand induced degradation using Shield- 1, ligand induced degradation using auxin, ligand induced degradation using rapamycin, peptidic degrons (e.g., IKZF3 based degrons), and proteolysistargeting chimeras (PROTACs). In some embodiments of a ligand induced degradation method, a degron tag that is held in an inactive conformation but is induced to adopt a conformation capable of recognition by the proteasome upon binding of a specific molecule, such as but not limited to, a Shield-1 molecule. See, e.g., Roth et al., Cellular Molecular Life Sciences, 2019, 76(14), 2761-2777, which is herein incorporated by reference in its entirety. Detailed descriptions of SMASH degron technology can be found in Hannah and Zhou, Nat Chem Biol, 2015, 11:637-638 and Chung et al., Nat Chem Biol, 2015, 11:713-720, which are herein incorporated by reference in their entireties. Detailed descriptions of LID degron technologies can be found in Bonger et al., Nat Chem Biol, 2011, 7(8):531 -7, which is herein incorporated by reference in its entirety.

[0251] In some embodiments, the inducible degron element is selected from the group consisting of a ligand inducible degron element such as a small molecule-assisted shutoff (SMASH) degron element. Shield- 1 responsive degron element, auxin responsive degron element, and rapamycin responsive degron element: a peptidic degron element: and a peptidic proteolysis targeting chimera (PROTAC) element. In useful embodiments, the ligandinducible degron element is a small molecule-assisted shutoff (SMASH) degron element and the exogenous factor for controlling immunogenicity is asunaprevir.

[0252] In some embodiments of a peptidic degron, a peptide tag is used that confers small molecule-mediated recruitment to an E3 ligase. In some embodiments, the peptide tag comprises the lymphoid-restricted transcription factor IKZF3 that is recruited to the E3 ligase receptor (CRBN) in an immunomodulatory drug (IMiD) dependent manner, as described in Koduri et al., Proc Natl Acad Sci, 2019, 116(7), 2539-2544, which is herein incorporated by reference in its entirety. In certain embodiments, the degron is capable of targeting immunosuppressive factors for degradation (e.g., through a ubiquitination pathway), inducing protein degradation, or degrading proteins.Pharmaceutical composition

[0253] In some embodiments, the 15-PGDH inhibitors described herein can be provided in a pharmaceutical composition. A pharmaceutical composition containing the 15-PGDH inhibitors described herein as an active ingredient may be manufactured by mixing the derivative with a pharmaceutically acceptable carrier(s) or an excipient(s) or diluting the 15-PGDH inhibitors with a diluent in accordance with conventional methods. The pharmaceutical composition may further contain fillers, anti-cohesives, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives and the like. The pharmaceutical composition may be formulated into a suitable formulation in accordance with the methods known to those skilled in the art so that it can provide an immediate, controlled or sustained release of the 15-PGDH inhibitors after being administered into a mammal.

[0254] In some embodiments, the pharmaceutical composition may be formulated into a parenteral or oral dosage form. The solid dosage form for oral administration may be manufactured by adding excipient, if necessary, together with binder, disintegrants, lubricants, coloring agents, and / or flavoring agents, to the 15-PGDH inhibitors and shaping the resulting mixture into the form of tablets, sugar-coated pills, granules, powder or capsules. The additives that can be added in the composition may be ordinary ones in the art. For example, examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate and the like. Exemplary binders include water, ethanol, propanol, sweet syrup, sucrose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphonate and polypyrrolidone.Examples of the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic monoglyceride and lactose. Further, purified talc, stearates, sodium borate, and polyethylene glycol may be used as a lubricant; and sucrose, bitter orange peel, citric acid, tartaric acid, may be used as a flavoring agent. In some embodiments, the pharmaceutical composition can be made into aerosol formulations (e.g., they can be nebulized) to be administered via inhalation.

[0255] The 15-PGDH inhibitors described herein may be combined with flavoring agents, buffers, stabilizing agents, and the like and incorporated into oral liquid dosage forms such as solutions, syrups or elixirs in accordance with conventional methods. One example of the buffers may be sodium citrate. Examples of the stabilizing agents include tragacanth, acacia and gelatin.

[0256] In some embodiments, the 15-PGDH inhibitors described herein may be incorporated into an injection dosage form, for example, for a subcutaneous, intramuscular or intravenous route by adding thereto pH adjusters, buffers, stabilizing agents, relaxants, topical anesthetics. Examples of the pH adjusters and the buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizing agents include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. The topical anesthetics may be procaine HC1, lidocaine HC1 and the like. The relaxants may be sodium chloride, glucose and the like.

[0257] In other embodiments, the 15-PGDH inhibitors described herein may be incorporated into suppositories in accordance with conventional methods by adding thereto pharmaceutically acceptable carriers that are known in the art, for example, polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, if necessary, together with surfactants such as Tween.

[0258] The pharmaceutical composition may be formulated into various dosage forms as discussed above and then administered through various routes including an oral, inhalational, transdermal, subcutaneous, intravenous or intramuscular route. The dosage can be a pharmaceutically or therapeutically effective amount.

[0259] Therapeutically effective dosages of 15-PDGH inhibitor is one that reduces activity and / or expression of 15-PGDH and treats the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granulomaformation, or with granulomatous inflammation, or with central necrosis and palisading macrophages.

[0260] In some embodiments, an optimum dosage of the 15-PGDH inhibitor and / or 15-PGDH substrate is one generating the maximum beneficial effect on damaged tissue. An effective dosage causes at least a statistically or clinically significant attenuation of at least one marker, symptom, or histological evidence characteristic of the inflammatory conditions, diseases and / or disorders characterized by macrophages associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages.

[0261] Therapeutically effective dosage amounts of the 15-PGDH inhibitor may be present in varying amounts in various embodiments. For example, in some embodiments, a therapeutically effective amount of the 15-PGDH inhibitor may be an amount ranging from about 10-1000 mg (e.g., about 20 mg-1,000 mg, 30 mg-1,000 mg, 40 mg-1,000 mg, 50 mg-1,000 mg, 60 mg-1,000 mg, 70 mg-1,000 mg, 80 mg-1,000 mg, 90 mg-1,000 mg, about 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-1000 mg, 200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 200-400 mg, 300-1000 mg, 300-900 mg, 300-800 mg, 300-700 mg, 300-600 mg, 300-500 mg, 400 mg-1,000 mg, 500 mg-1,000 mg, 100 mg-900 mg, 200 mg-800 mg, 300 mg-700 mg, 400 mg-700 mg, and 500 mg-600 mg). In some embodiments, the 15-PGDH inhibitor is present in an amount of or greater than about 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. In some embodiments, the 15-PGDH inhibitor is present in an amount of or less than about 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg.

[0262] In other embodiments, a therapeutically effective dosage amount may be, for example, about 0.001 mg / kg weight to 500 mg / kg weight, e.g., from about 0.001 mg / kg weight to 400 mg / kg weight, from about 0.001 mg / kg weight to 300 mg / kg weight, from about 0.001 mg / kg weight to 200 mg / kg weight, from about 0.001 mg / kg weight to 100 mg / kg weight, from about 0.001 mg / kg weight to 90 mg / kg weight, from about 0.001 mg / kg weight to 80 mg / kg weight, from about 0.001 mg / kg weight to 70 mg / kg weight, from about 0.001 mg / kg weight to 60 mg / kg weight, from about 0.001 mg / kg weight to 50 mg / kg weight,from about 0.001 mg / kg weight to 40 mg / kg weight, from about 0.001 mg / kg weight to 30 mg / kg weight, from about 0.001 mg / kg weight to 25 mg / kg weight, from about 0.001 mg / kg weight to 20 mg / kg weight, from about 0.001 mg / kg weight to 15 mg / kg weight, from about 0.001 mg / kg weight to 10 mg / kg weight.

[0263] In still other embodiments, a therapeutically effective dosage amount may be, for example, about 0.0001 mg / kg weight to 0.1 mg / kg weight, e.g. from about 0.0001 mg / kg weight to 0.09 mg / kg weight, from about 0.0001 mg / kg weight to 0.08 mg / kg weight, from about 0.0001 mg / kg weight to 0.07 mg / kg weight, from about 0.0001 mg / kg weight to 0.06 mg / kg weight, from about 0.0001 mg / kg weight to 0.05 mg / kg weight, from about 0.0001 mg / kg weight to about 0.04 mg / kg weight, from about 0.0001 mg / kg weight to 0.03 mg / kg weight, from about 0.0001 mg / kg weight to 0.02 mg / kg weight, from about 0.0001 mg / kg weight to 0.019 mg / kg weight, from about 0.0001 mg / kg weight to0.018 mg / kg weight, from about 0.0001 mg / kg weight to 0.017 mg / kg weight, from about 0.0001 mg / kg weight to 0.016 mg / kg weight, from about 0.0001 mg / kg weight to0.015 mg / kg weight, from about 0.0001 mg / kg weight to 0.014 mg / kg weight, from about 0.0001 mg / kg weight to 0.013 mg / kg weight, from about 0.0001 mg / kg weight to0.012 mg / kg weight, from about 0.0001 mg / kg weight to 0.011 mg / kg weight, from about 0.0001 mg / kg weight to 0.01 mg / kg weight, from about 0.0001 mg / kg weight to 0.009 mg / kg weight, from about 0.0001 mg / kg weight to 0.008 mg / kg weight, from about 0.0001 mg / kg weight to 0.007 mg / kg weight, from about 0.0001 mg / kg weight to 0.006 mg / kg weight, from about 0.0001 mg / kg weight to 0.005 mg / kg weight, from about 0.0001 mg / kg weight to 0.004 mg / kg weight, from about 0.0001 mg / kg weight to 0.003 mg / kg weight, from about 0.0001 mg / kg weight to 0.002 mg / kg weight. In some embodiments, the therapeutically effective dose may be 0.0001 mg / kg weight, 0.0002 mg / kg weight, 0.0003 mg / kg weight, 0.0004 mg / kg weight, 0.0005 mg / kg weight, 0.0006 mg / kg weight, 0.0007 mg / kg weight, 0.0008 mg / kg weight, 0.0009 mg / kg weight, 0.001 mg / kg weight, 0.002 mg / kg weight, 0.003 mg / kg weight, 0.004 mg / kg weight, 0.005 mg / kg weight, 0.006 mg / kg weight, 0.007 mg / kg weight, 0.008 mg / kg weight, 0.009 mg / kg weight, 0.01 mg / kg weight, 0.02 mg / kg weight, 0.03 mg / kg weight, 0.04 mg / kg weight, 0.05 mg / kg weight, 0.06 mg / kg weight, 0.07 mg / kg weight, 0.08 mg / kg weight, 0.09 mg / kg weight, or 0.1 mg / kg weight. The effective dose for a particular individual can be varied (e.g., increased or decreased) over time, depending on the needs of the individual.

[0264] In some embodiments, a therapeutically effective dosage may be a dosage of 10 pg / kg / day, 50 pg / kg / day, 100 pg / kg / day, 250 pg / kg / day, 500 pg / kg / day, 1000 pg / kg / day or more. In various embodiments, the amount of the 15-PGDH inhibitor or pharmaceutical salt thereof is sufficient to provide a dosage to a patient of between 0.01 pg / kg and 10 pg / kg; 0.1 pg / kg and 5 pg / kg; 0.1 pg / kg and 1000 pg / kg; 0.1 pg / kg and 900 pg / kg; 0.1 pg / kg and 900 pg / kg; 0.1 pg / kg and 800 pg / kg; 0.1 pg / kg and 700 pg / kg; 0.1 pg / kg and 600 pg / kg; 0.1 pg / kg and 500 pg / kg; or 0.1 pg / kg and 400 pg / kg.

[0265] Particular doses or amounts to be administered in accordance with the present invention may vary, for example, depending on the nature and / or extent of the desired outcome, on particulars of route and / or timing of administration, and / or on one or more characteristics (e.g., weight, age, personal history, genetic characteristic, lifestyle parameter, etc., or combinations thereof). Such doses or amounts can be determined by those of ordinary skill. In some embodiments, an appropriate dose or amount is determined in accordance with standard clinical techniques. For example, in some embodiments, an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8. 9, 10, 11, 12, 13. 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or more. For example, in some embodiments, an appropriate dose or amount is a dose or amount sufficient to reduce a disease severity index score by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%. Alternatively, or additionally, in some embodiments, an appropriate dose or amount is determined through use of one or more in vitro or in vivo assays to help identify desirable or optimal dosage ranges or amounts to be administered.

[0266] Various embodiments may include differing dosing regimen. In some embodiments, the 15-PGDH inhibitor and / or 15-PGDH substrate can be administered via continuous infusion. In some embodiments, the continuous infusion is intravenous. In other embodiments, the continuous infusion is subcutaneous. Alternatively, or additionally, in some embodiments, the 15-PGDH inhibitor can be administered bimonthly, monthly, twice monthly, triweekly, biweekly, weekly, twice weekly, thrice weekly, daily, twice daily, or on another clinically desirable dosing schedule. The dosing regimen for a single subject need not be at a fixed interval, but can be varied over time, depending on the needs of the subject.

[0267] For topical application, the composition can be administered in the form of aqueous, alcoholic, aqueous-alcoholic or oily solutions or suspensions, or of a dispersion of the lotion or serum type, of emulsions that have a liquid or semi-liquid consistency or are pasty, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or vice versa (W / O) or multiple emulsions, of a free or compacted powder to be used as it is or to be incorporated into a physiologically acceptable medium, or else of microcapsules or microparticles, or of vesicular dispersions of ionic and / or nonionic type. It may thus be in the form of a salve, a tincture, milks, a cream, an ointment, a powder, a patch, an impregnated pad, a solution, an emulsion or a vesicular dispersion, a lotion, aqueous or anhydrous gels, a spray, a suspension, a shampoo, an aerosol or a foam. It may be anhydrous or aqueous. It may also comprise solid preparations constituting soaps or cleansing cakes.Combination Therapy

[0268] Other embodiments described herein relate to (i) methods of treatment and uses as previously described that further comprise the administration of one or more additional therapeutic agents (i.e., combination therapies), and (ii) pharmaceutical compositions as previously described that further comprise one or more additional therapeutic agents (i.e., fixed-dose combinations). When administered to a subject in combination with one or more additional therapeutic agents, the 15-PGDH inhibitor and the additional therapeutic agent(s) can be administered as separate dosage forms or as a single dosage form comprising the 15-PGDH inhibitor and the additional therapeutic agent(s). If administered as a separate dosage form, the additional therapeutic agent may be administered either simultaneously with, or sequentially with, the dosage form comprising the 15-PGHD.

[0269] In some embodiments, pharmaceutical compositions including the 15-PGDH inhibitor described herein can additionally contain, for example, at least one 15-PGHD substrate chosen from prostaglandins, in particular prostaglandin PGE1, PGE2, their salts, their esters, their analogues and their derivatives, in particular those described in WO 98 / 33497, WO 95 / 11003, JP 97-100091, JP 96-134242, in particular agonists of the prostaglandin receptors. It may in particular contain at least one compound such as the agonists (in acid form or in the form of a precursor, in particular in ester form) of the prostaglandin F2α receptor, such as for example latanoprost, fluprostenol, cloprostenol, bimatoprost, unoprostone, the agonists (and their precursors, in particular the esters such as travoprost) of the prostaglandin E2receptors such as 17-phenyl PGE2, viprostol, butaprost,misoprostol, sulprostone, 16, 16-dimethyl PGE2, 11-deoxy PGE1, 1-deoxy PGE1, the agonists and their precursors, in particular esters, of the prostacycline (IP) receptor such as cicaprost, iloprost, isocarbacycline, beraprost, eprostenol, treprostinil, the agonists and their precursors, in particular the esters, of the prostaglandin D2receptor such as BW245C ((4S)-(3-[(3R, S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), BW246C ((4R)-(3-[(3R, S)-3-cyclohexyl-3-isopropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid), the agonists and their precursors, in particular the esters, of the receptor for the thromboxanes A2 (TP) such as I-BOP ([LS-[la,2a(Z), 3b(lE,3S),4a]]-7-[3-[3-hydroxy-4-[4-(iodophenoxy)-l-butenyl]-7-oxabicyclo- [2.2.1]hept-2-yl]-5-heptenoic acid).

[0270] Advantageously, the composition can include at least one 15-PGDH inhibitor as defined above and at least one prostaglandin or one prostaglandin derivative such as for example the prostaglandins of series 2 including in particular PGF2α and PGE2in saline form or in the form of precursors, in particular of the esters (example isopropyl esters), their derivatives such as 16, 16-dimethyl PGE2, 17-phenyl PGE2 and 16,16-dimethyl PGF201 17-phenyl PGF2a, prostaglandins of series 1 such as 11 -deoxyprostaglandin El, 1-deoxyprostaglandin El in saline or ester form, is their analogues, in particular lat anoprost, travoprost, fluprostenol, unoprostone, bimatoprost, cloprostenol, viprostol, butaprost, misoprostol, their salts or their esters.

[0271] In other embodiments, the 15-PGDH inhibitor may be administered in combination with one or more additional agents that modulate a mammalian immune system or with anti-inflammatory agents. These agents may include but are not limited to cyclosporin A (e.g., SANDIMMUNE® or NEORAL®, rapamycin, FK-506 (tacrolimus), leflunomide, dcoxyspcrgualin, mycophcnolatc (e.g., CELLCEPT®), azathioprinc (e.g., IMURAN®), daclizumab (e.g.. ZENAPAX®), OKT3 (e.g., ORTHOCLONE®), AtGam, aspirin, acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid, metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). In certain embodiments, the one or more additional agents are selected from the group consisting of aspirin, acetaminophen, aminosalicylate, ciprofloxacin, corticosteroid, cyclosporine, metronidazole, probiotic, tacrolimus, ibuprofen, naproxen, piroxicam, prednisolone, dexamethasone, anti-inflammatory steroid, methotrexate, chloroquine, azathioprine, hydroxychloroquine, penicillamine, sulfasalazine, leflunomide, tocilizumab, anakinra, abataccpt, ccrtolizumab pcgol, golimumab, vcdolizumab, natalizumab,ustekinumab, rituximab, efalizumab, belimumab, etanercept, infliximab, adalimumab, and immune modulator (e.g., activator) for CD4+CD25+ Treg cells.

[0272] Other examples of therapeutic agents that can be administered in combination with the 15-PGDH inhibitor described herein can include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL- 12, IL- 15, IL- 16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. Compounds of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L). Combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade. Such examples may include TNF antagonists like chimeric, humanized or human TNF antibodies, adalimumab (such as HUMIRA™ brand adalimumab), infliximab such as CA2 (REMICADE™ brand infliximab), golimumab such as SIMPONI™ (golimumab), certolizumab pegol such as CIMZIA™, tocilizumab such as ACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, etanercept such as p75TNFRlgG (ENBREL™ brand etanercept) or p55TNFRlgG (lenercept), and also TNFa converting enzyme (TACE) inhibitors; similarly IL-1 inhibitors (Interleukin- 1 -converting enzyme inhibitors, IL- IRA etc.) may be effective for the same reason. Other combinations include Interleukin 11.

[0273] The 15-PGDH inhibitor described herein can also be combined with nonbiologic DMARDS or other agents, such as methotrexate, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazinc chloroquinine / hydroxychloroquine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeterol), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1β convertingenzyme inhibitors, T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, and 6-mercaptopurines.

[0274] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims. All patents, publications and references cited in the foregoing specification are herein incorporated by reference in their entirety.

Claims

What is claimed is:

1. A method of treating an inflammatory disease that is characterized by macrophages in a subject in need thereof, the method comprising:administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.

2. The method of claim 1, wherein the macrophages express 15-PGDH.

3. The method of claim 1 or 2, wherein the macrophages are associated with giant cells, or with granuloma formation, or with granulomatous inflammation, or with central necrosis and palisading macrophages.

4. The method of any of claims 1 to 3, wherein the inflammation is associated with oxidative tissue damage.

5. The method of any of claims 1 to 4, wherein the inflammatory disease is any of arteritis, vascular inflammation, giant cell arteritis, sarcoidosis, rheumatoid arthritis, or other conditions associated with inflammatory macrophages or associated with macrophages and oxidative tissue damage.

6. The method of any of claims 1 to 5, wherein the 15-PGDH inhibitor is administered to the subject at an amount effective to block aberrantly increased 15-PGDH enzymatic activity.

7. The method of any of claims 1 to 6, wherein the 15-PGDH inhibitor is a small molecule that binds to 15-PGDH protein.

8. The method of any of claims 1 to 7, wherein the 15-PGDH inhibitor can inhibit enzymatic activity of recombinant 15-PGDH at an IC50of less than 1 μM, or preferably at an IC50of less than 250 nM, or more preferably at an IC50of less than 50 nM, or more preferably at an IC50of less than 10 nM, or more preferably at an IC50of less than 5nM, or more preferably at an IC50of less than 5 nM at a recombinant 15-PGDH concentration of about 5 nM to about 10 nM.

9. The method of any of claims 1 to 6, wherein the 15-PGDH inhibitor is a molecule or generates a molecule that binds to 15-PGDH mRNA to promote degradation 15-PGDH mRNA and / or inhibit expression of 15-PGDH.

10. The method of claim 9, wherein the molecule comprises an RNA interference (RNAi) molecule, preferably at least one of a small interfering RNA (siRNA) or microRNA (miRNA).

11. The method of any of claims 1 to 6, wherein the 15-PGDH inhibitor comprises an agent or method of gene editing that inactivates or alters the HPGD gene that encodes 15-PGDH.

12. The method of claim 11, wherein the 15-PGDH inhibitor comprises at least one nuclease that can remove, cut, or alter a target nucleic acid sequence of the HPGD gene.

13. The method of any of claims 1 to 6, wherein the 15-PGDH inhibitor is an agent that promotes the degradation of 15-PGDH protein.

14. The method of claim 13, wherein the agent comprises at least one of a small molecule-assisted shutoff (SMASH) system, a Shield- 1 -inducible degron, an auxin inducible degron, an IMid-inducible degron, a peptidic degron, a proteolysis targeting chimera, or an antibody for targeted 15-PGDH degradation.

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