Amiprilose (SM 1213) has anti-inflammatory activity and inhibits the proliferation of a variety of hyperproliferative cell types.Amiprilose induces lymphokine-induced macrophage activation and may be used in studies of rheumatoid arthritis and psoriasis.

NHWD-870 is an effective and selective inhibitor of BET family bromodomain only binding to BRD2, BRD3, BRD4 (IC50 = 2.7 nM), and BRDT. NHWD-870 exhibits potent anti-tumor efficacies and suppresses cancer cell-macrophage interaction through the increase of tumor apoptosis and inhibition of tumor proliferation.

Talabostat (PT100, Val-boroPro) is a potent, nonselective and orally available dipeptidyl peptidase IV (DPP-IV) inhibitor with a Ki of 0.18 nM. Talabostat is a nonselective DPP-IV inhibitor, inhibiting DPP8/9, FAP, DPP2 and some other DASH family enzymes essentially as potently as it inhibits DPP-IV[1]. Talabostat stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. The inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC[2]. Talabostat competitively inhibits the dipeptidyl peptidase (DPP) activity of FAP and CD26/DPP-IV, and there is a high-affinity interaction with the catalytic site due to the formation of a complex between Ser630/624 and the boron of talabostat[3]. Talabostat can stimulate immune responses against tumors involving both the innate and adaptive branches of the immune system. In WEHI 164 fibrosarcoma and EL4 and A20/2J lymphoma models, PT-100 causes regression and rejection of tumors. The antitumor effect appears to involve tumor-specific CTL and protective immunological memory. Talabostat treatment of WEHI 164-inoculated mice increases mRNA expression of cytokines and chemokines known to promote T-cell priming and chemoattraction of T cells and innate effector cells[3]. Talabostat treated mice show significant less fibrosis and FAP expression is reduced. Upon PT100 treatment, significant differences in the MMP-12, MIP-1α, and MCP-3 mRNA expression levels in the lungs are also observed. Treatment with PT100 in this murine model of pulmonary fibrosis has an anti-fibro-proliferative effect and increases macrophage activation[4]. [1]. Connolly BA, et al. Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potencyand in vivo efficacy and safety. J Med Chem. 2008 Oct 9;51(19):6005-13. [2]. Okondo MC, et al. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017 Jan;13(1):46-53. [3]. Adams S, et al. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004 Aug 1;64(15):5471-80. [4]. Egger C, et al. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur J Pharmacol. 2017 Aug 15;809:64-72.

Bestatin (Ubenimex) competitively inhibits many aminopeptidases, including B, N and leucine aminopeptidases. Ubenimex is a microbial metabolite and dipeptide with potential immunomodulatory and antitumor activities. Aminopeptidases has been implicated in the process of cell adhesion and invasion of tumor cells. Therefore, inhibiting aminopeptidases may partially attribute to the antitumor effect of ubenimex. This agent also activates T lymphocyte, macrophage, and bone marrow stem cell as well as stimulates the release of interleukin-1 and -2, thus further enhances its antitumor activity.

D-Trimannuronic acid is an alginate oligomer that originates from seaweed. It can induce TNF-α secretion by mouse macrophage cell lines, making it valuable in pain and vascular dementia research [1][2][3].

Murlentamab (GM102) is a humanized anti-AMhRII antibody. Murlentama has potential antitumor activity that induces macrophage-mediated antitumor-dependent cell-mediated cytotoxic effects (ADCC). Murl can stimulate the pro-inflammatory and anti-tumor internal environment by recruiting, collecting and activating T cells. Murlentama exerts antitumor activity by promoting naive macrophage orientation and promoting tumor-associated macrophage (TAM) reprogramming.

Betamethasone 21-phosphate is a synthetic glucocorticoid.1It prevents increases in macrophage and eosinophil numbers in bronchoalveolar lavage fluid (BALF) and decreases in blood leukocyte numbers in a guinea pig model of parainfluenza-3 viral infection when administered at a dose of 8 mg/kg but does not prevent airway hyperresponsiveness after infection.2Betamethasone 21-phosphate inhibits cell infiltration into the aqueous humor in a rat model of endotoxin-induced uveitis when administered topically or subcutaneously at doses of 0.01-1% or 1 mg/kg, respectively.3It increases maximal lung pressure volume curves in fetal sheep when administered to pregnant ewes at 0.75 gestation at doses of 80 and 170 μg/kg.1Betamethasone 21-phosphate increases body weight, impairs learning and memory, increases anxiolytic behavior, and reduces hippocampal neurogenesis in CD-1 mice but reduces body weight and increases neurogenesis with no effect on anxiety in high-anxiety DBA/2 mice when administered at a dose of approximately 25 mg/kg per day in the drinking water for seven weeks.4Formulations containing betamethasone 12-phosphate and betamethasone acetate have been used in the treatment of severe allergic conditions and a variety of immune-related conditions. 1.Loehle, M., Schwab, M., Kadner, S., et al.Dose-response effects of betamethasone on maturation of the fetal sheep lungAm. J. Obstet. Gynecol.202(2)186.e181-186.e187(2010) 2.Leusink-Muis, A., Ten Broeke, R., Folkerts, G., et al.Betamethasone prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigsClin. Exp. Allergy29(Suppl. 2)82-85(1999) 3.Tsuji, F., Sawa, K., Kato, M., et al.The effects of betamethasone derivatives on endotoxin-induced uveitis in ratExp. Eye Res.64(1)31-36(1997) 4.Aiello, R., Crupi, R., Leo, A., et al.Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesisBehav. Brain Res.278155-166(2015)

Otilimab (GSK 3196165) is a humanized monoclonal antibody against granulocyt-macrophage colony-stimulating factor (GM-CSF). Otilimab has anti-inflammatory activity, regulates the biological function of GM-CSF by blocking the interaction between GM-CSF and its cell surface receptors, and can be used in studies to treat severe COVID-19 pneumonia.

Roquinimex (FCF89) (Linomide) is a quinoline derivative immunostimulant which increases NK cell activity and macrophage cytotoxicity; inhibits angiogenesis and reduces the secretion of TNF alpha.

Anzurstobart (CC-95251; BMS-986351), a fully human monoclonal anti-SIRPα antibody with high affinity, inhibits CD47-SIRPα interaction. It potentiates macrophage-mediated phagocytosis of DLBCL cell lines in co-culture assays with Rituximab and shows promise in solid and hematologic malignancy research [1].

MKA031 (compound 6y) is a non-competitive inhibitor of macrophage migration inhibitory factor (MIF), exhibiting an IC50 of 1.7 μM. It disrupts the MIF-aryl hydrocarbon receptor interacting protein (AIF) interaction, impedes MIF nuclear translocation, and mitigates N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced cell death. MKA031 is applicable in research on chronic hepatitis C virus infection [1].

Thiocarlide (isoxyl) is a thiourea derivative that was used in the 1960s to successfully treat tuberculosis (TB). It has considerable antimycobacterial activity in vitro and is effective against multi-drug resistant strains of Mycobacterium tuberculosis in the range of 1-10 µg/ml. [1] [2] At concentrations of 10 µM, isoxyl inhibits the synthesis of M. bovis during six hours of exposure which is similar to isoniazid (INH) and ethionamide (ETH), two other predominant anti-tuberculosis drugs. Unlike INH and ETH, isoxyl also partially inhibits the synthesis of fatty acids. Isoxyl shows no acute toxicity against primary macrophage cell cultures as demonstrated by diminution of redox activity.[2]

Amivantamab (JNJ-61186372) is a bispecific antibody targeting EGFR-MET with immune anticancer properties. It prevents ligand binding, enhances receptor-antibody complex endocytosis and degradation, and triggers Fc-mediated macrophage cytokinesis and natural killer cell antibody-dependent cytotoxicity [1].

LYP-IN-3 (compound D34) is a selective Lymphoid-tyrosine phosphatase (LYP) inhibitor (Ki=0.93 μM) that modulates the T-cell receptor (TCR) signaling pathway during tumor progression. It promotes T-cell activation, hinders M2 macrophage polarization, and increases PD-1/PD-L1 expression. When combined with PD-1/PD-L1 inhibitors, LYP-IN-3 may enhance cancer immunotherapy [1].

Inosine pranobex (Delimmun) has a number of immunomodulatory effects, including inducing T-lymphocyte differentiation, augmenting macrophage and NK cell functions, and stimulating IL-2 production. Through these effects and others, isoprinosine shows antiviral activity and has applications against subacute sclerosing panencephalitis. It also restores depressed immune responses in Y patients after irradiation and reduces the incidence of infection in leukemia patients undergoing chemotherapy. It is most commonly used to treat the rare measles complication subacute sclerosing panencephalitis in conjunction with intrathecal interferon therapy.

Cimifugin (Cimitin) inhibits NO production induced by lipopolysaccharide in macrophage cell line RAW 264.7 and for 1, 1-diphenyl-2-picrylhydrazyl free-radical scavenging activity in cell-free bioassay system.

EP4 antagonist 14 is a prostaglandin E2 receptor subtype EP4 antagonist, demonstrating an IC50 of 1.1 nM in a HEK293 human receptor reporter assay and blocking β-arrestin recruitment due to PGE2 with an IC50 of 0.9 nM. At 10 µM, it reduces PGE2-stimulated mRNA levels of Il-4, macrophage mannose receptor 1 (Mrc1), chitinase-like protein 3 (Chil3), chemokine (C-X-C) motif ligand 1 (Cxcl1), triggering receptor expressed on myeloid cells 2 (Trem2), and arginase-1 (Arg1) in RAW 264.7 macrophages. When used at 30 mg/kg per day alongside anti-PD-1 antibodies, it curbs tumor growth and enhances CD8+ T cell infiltration in tumors using a CT26 murine colon cancer model.

LYP-IN-4 (compound D14), a reversible and selective lymphotyrosine phosphatase (LYP) inhibitor (Ki=1.34 μM, IC50=3.52μM), regulates TCR signaling, increases PD-1/PD-L1 expression, and strengthens anti-tumor immunity. It also stimulates T cell activation, impedes M2 macrophage polarization, and suppresses tumor progression in MC38 isogenic mouse models.

MIF-IN-6 (compound 2d) is an effective inhibitor of macrophage migration inhibitory factor (MIF), exhibiting an IC50 of 1.4 μM and a Ki value of 0.96 μM. MIF-IN-6 effectively reduces MIF-induced ERK phosphorylation and impedes A549 cell proliferation [1].

JC-171, a selective inhibitor of the NLRP3 inflammasome, effectively inhibits LPS/ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 μM[1].

Cochlioquinone A is an inhibitor of diacylglycerol kinase (DGK) and diacylglycerol acyltransferase (DGAT). It has been shown to reduce the concentration of phosphatidic acid in T cell lymphoma and has also been shown to compete with macrophage inflammatory protein-1α for binding to human CCR5 chemokine receptors.

Matrix metalloproteinase-3 (MMP-3), also known as stromelysin-1, is a critical enzyme involved in tissue remodeling and repair through its role in degrading extracellular matrix proteins, facilitating cell migration. This enzyme has been implicated in various physiological processes including vascular remodeling associated with aneurysm formation, wound healing, the progression of atherosclerosis, and tumor initiation. MMP-3 inhibitor VIII, a cell-permeable sulfonamide-based hydroxamic acid, effectively inhibits MMP-3 by binding to its active site (Ki = 23 nM), thus blocking its enzymatic activity. Additionally, this inhibitor has been demonstrated to suppress the activity of mouse macrophage metalloelastase MME/MMP-12, with an IC50 value of 13 nM, highlighting its potential utility in research on tissue remodeling and disease processes involving MMPs.

PPM-3, a selective PROTAC ERK5 degrader, exhibits a potent inhibitory concentration (IC 50) of 62.4 nM. While not directly inhibiting tumor cell growth, PPM-3 affects tumor progression through influencing macrophage differentiation [1].

Glutinol acetate shows significant cytotoxic activity against four human cancer cell lines (HL-60, SK-OV-3, A549, and HT-29), with GI(50) in the range of 11.1-17.9microM; it also has anti-inflammatory effect, exhibits moderate inhibitory activity of TNF-alpha secretion in the lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cell line.

GGTI-2166 is a geranylgeranyl transferase I inhibitor. GGTI-2166 inhibit the pOC formation induced by RANKL or TNF-alpha in cultures of both mouse marrow-derived macrophage-colony-stimulating factor (M-CSF) dependent monocytes (MD cells) and the mouse monocyte cell line RAW 264.7 (RAW cells). GGTI-2166 inhibited TRAP activity induced by RANKL or TNF-alpha in both cell cultures and prevented the incorporation of [3H]all-trans geranylgeraniol into prenylated proteins in RAW cells.

MIF098 is a macrophage migration inhibitory factor (MIF) antagonist.MIF098, inhibits pulmonary hypertension associated with SLE and inhibits pulmonary smooth muscle cell (PASMC) proliferation and migration.MIF098 may be used to study idiopathic pulmonary hypertension.

Futokadsurin C can inhibit nitric oxide production by a murine macrophage-like cell line (RAW 264.7), which is activated by lipopolysaccharide and interferon-gamma.

Fargesone A shows inhibitory effects on nitric oxide (NO) production in the lipopolysaccharide plus interferon-gamma activated-murine macrophage cell line, J774.1.

Golotimod hydrochloride (SCV 07 hydrochloride) is an immunomodulating peptide with antimicrobial properties. It enhances antituberculosis therapy effectiveness, promotes thymic and splenic cell proliferation, and boosts macrophage functionality. Furthermore, it inhibits STAT3 signaling, thereby modifying the duration and intensity of oral mucositis in animal models subjected to radiation or a combination of radiation and Cisplatin. Additionally, Golotimod hydrochloride has shown potential as a treatment for recurrent genital herpes simplex virus type 2 (HSV-2) [1] [2] [3].

1,3,9-Trimethyluric acid exhibits in vitro cytotoxic activity against breast cancer (MCF-7), human neuroblastoma (SHSY5Y), human non-small cell lung cancer (A549) and human liver cancer (HEPG2) with IC50 value in the range of 1-3 uM. 1,3,9-Trimethyluric a

CCR4 antagonist 3-1 is a less active chemokine receptor 4 (CCR4) antagonist that inhibits [125I]TARC (thymus and activation-regulated chemokine) with an IC50 value of 1.7 μM. CCR4 antagonist 3-1 inhibits the binding of radiolabeled [125I]TARC and macrophage-derived chemokine ( MDC) to CEM cell surface and inhibits TARC-mediated CEM cell migration in vitro with an IC50 value of 6.4 μM. CCR4 antagonist 3 inhibited the binding of radiolabeled [125I]TARC and macrophage-derived chemokine (MDC) to the CCR4 receptor on the surface of CEM cells and inhibited TARC-mediated migration of CEM cells in vitro with an IC50 value of 6.4 μM.

EZH2/EPP interaction inhibitor (Kd = 320 nM). Suppresses EZH2 expression and H3K27 trimethylation by PCR2 complex. Arrests proliferation and induces monocyte to macrophage differentiation of MLL-AF9 leukemia cell line.

KGP94 is an inhibitor of cysteine protease Cathepsin L(CTSL).

Golotimod (SCV 07) is an antimicrobial dipeptide with immunomodulatory activity that significantly improves the efficacy of anti-tuberculosis therapy, induces thymic and splenic cell proliferation, modulates macrophage function, and inhibits STAT3 signaling.Golotimod has been used in the study of recurrent genital Herpes Simplex Virus 2 (HSV-2) infection and oral mucositis.

G150 inhibited interferon expression triggered by DSDNA with IC50 of 10.2 nM.G150 is an effective and highly selective inhibitor of human cyclic GMP-AMP synthase (H-CGAS).