t 100

KRN2 bromide is a potent, selective inhibitor of nuclear factor of activated T cells (NFAT5, IC50= 0.1 μM).

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.

Adenosine 5’-methylenediphosphate is an inhibitor of ecto-5’-nucleotidase, also known as CD73, with a Kivalue of 37 nM.1It inhibits cAMP accumulation induced by adenosine 5’-monophosphate , adenosine 5’-diphosphate , or adenosine 5’-triphosphate but not adenosine in VA-13 human fibroblasts when used at a concentration of 100 μM. Adenosine 5’-methylenediphosphate reduces proliferation of U138MG glioma cells, as well as inhibits the invasion and migration of MHCC97H hepatocellular carcinoma (HCC) cells in a migration assay.2,3It increases tumor infiltration of CD3+CD8+T cells and reduces tumor growth in a K1735 murine melanoma model when administered at a dose of 400 μg/mouse.4 1.Bruns, R.F.Adenosine receptor activation by adenine nucleotides requires conversion of the nucleotides to adenosineNaunyn Schmiedebergs Arch. Pharmacol.315(1)5-13(1980) 2.Braganhol, E., Tamajusuku, A.S.K., Bernardi, A., et al.Ecto-5′-nucleotidase/CD73 inhibition by quercetin in the human U138MG glioma cell lineBiochim. Biophys. Acta1770(9)1352-1359(2007) 3.Shali, S., Yu, J., Zhang, X., et al.Ecto\5′\nucleotidase (CD73) is a potential target of hepatocellular carcinomaJ. Cell Physiol.234(7)10248-10259(2018) 4.Forte, G., Sorrentino, R., Montinaro, A., et al.Inhibition of CD73 improves B cell-mediated anti-tumor immunity in a mouse model of melanomaJ. Immunol.189(5)2226-2233(2021)

PAR2 (1-6) amide is a synthetic peptide agonist of proteinase-activated receptor 2 (PAR2) that corresponds to residues 1-6 of the amino terminal tethered ligand sequence of human PAR2 and residues 37-42 of the full-length sequence.1It binds to NCTC 2544 cells expressing human PAR2 (Ki= 9.64 μM in a radioligand binding assay) and induces calcium mobilization in the same cells (EC50= 0.075 μM).2PAR2 (1-6) amide (100 μM) reduces colony formation of A549 lung cancer cells.1It induces superoxide production and degranulation in isolated human eosinophils when used at a concentration of 500 μM.3PAR2 (1-6) amide (5 μmol/kg) induces tear secretion in rats when used in combination with amastatin .4 1.Bohm, S.K., Kong, W., Bromme, D., et al.Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2Biochem. J.314(Pt 3)1009-1016(1996) 2.Kanke, T., Ishiwata, H., Kabeya, M., et al.Binding of a highly potent protease-activated receptor-2 (PAR2) activating peptide, [3H]2-furoyl-LIGRL-NH2, to human PAR2Br. J. Pharmacol.145(2)255-263(2005) 3.Miike, S., McWilliam, A.S., and Kita, H.Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2J. Immunol.167(11)6615-6622(2001) 4.Nishikawa, H., Kawai, K., Tanaka, M., et al.Protease-activated receptor-2 (PAR-2)-related peptides induce tear secretion in rats: Involvement of PAR-2 and non-PAR-2 mechanismsJ. Pharmacol. Exp. Ther.312(2)324-331(2005)

C8 Galactosylceramide is a synthetic C8 short-chain derivative of known membrane microdomain-forming sphingolipids. It increases the amount delivered and toxicity of doxorubicin in cancerous but not non-cancerous cells when incorporated into the nanoliposomal membrane of nanoliposomal-doxorubicin. C8 Galactosylceramide induces proliferation and cytokine production by splenocytes in vitro at concentrations ranging from 100-1,000 ng/ml but has no effect on natural killer T cell production in vivo. It also activates NF-κB production in C6 glioma cells when used at a concentration of 10 μM.

Pericosine A is a fungal metabolite that has been found inP. byssoidesand has anticancer activity.1It inhibits the growth of a variety of cancer cells, including breast, colon, lung, ovary, stomach, and prostate cell lines (GI50s = 0.05-24.55 μM) and increases survival in a P388 mouse xenograft model when administered at a dose of 25 mg/kg. Pericosine A inhibits EGFR by 40 to 70% when used at a concentration of 100 μg/ml. It also reacts with organosulfur compounds in skunk spray to form stable thioethers as odorless products.2 1.Yamada, T., Iritani, M., Ohishi, H., et al.Pericosines, antitumour metabolites from the sea hare-derived fungus Periconia byssoides. Structures and biological activitiesOrg. Biomol. Chem.5(24)3979-3986(2007) 2.Du, L., Munteanu, C., King, J.B., et al.An electrophilic natural product provides a safe and robust odor neutralization approach to counteract malodorous organosulfur metabolites encountered in skunk sprayJ. Nat. Prod.82(7)1989-1999(2019)

Altemicidin is a monoterpene alkaloid originally isolated fromS. sioyaensiswith acaricidal and anticancer activities.1It is acaricidal to two-spotted spider mites (T. urticae) in a greenhouse pot test at concentrations of 10 and 100 ppm. Altemicidin inhibits the growth of murine L1210 lymphocytic leukemia and IMC carcinoma cells (IC50s = 0.84 and 0.82 μg/ml, respectively). It is toxic to mice with an LD50value of 0.3 mg/kg. 1.Takahashi, A., Kurasawa, S., Ikeda, D., et al.Altemicidin, a new acaricidal and antitumor substance. I. Taxonomy, fermentation, isolation and physico-chemical and biological propertiesJ. Antibiot. (Tokyo)42(11)1556-1561(1989)

AP39 is a compound used to increase the levels of hydrogen sulfide (H2S) within mitochondria. It consists of a mitochondria-targeting motif (triphenylphosphonium) coupled to an H2S-donating moiety (dithiolethione) by an aliphatic linker. AP39 (30-300 nM) dose-dependently increases H2S levels in endothelial cells, predominantly in mitochondrial regions. It stimulates mitochondrial electron transport and improves cellular bioenergetic function at lower concentrations (30-100 nM), while having an inhibitory effect at 300 nM. Under oxidative stress conditions induced by glucose oxidase, AP39 has antioxidant and cytoprotective effects. AP39 is effective in vivo, inhibiting voltage-dependent T-type calcium channels and improving hemodynamic parameters in rats.

Petromurin C is a bis-indolyl benzenoid fungal metabolite originally isolated from the ascostromata of P. muricatus. It is cytotoxic to NS-1 mouse myeloma cells (IC50 = 33 μg/ml) and has activity against T. foetus in vitro (IC50 = 100 μg/ml).

Piericidin B is a bacterial metabolite that has been found inS. mobaraensisand has insecticidal and antimicrobial activities.1,2,3It inhibits NADH oxidase activity in isolated bovine heart mitochondria and inhibits respiration in isolated rat liver mitochondria and isolated cockroach (P. americana) muscle mitochondria.2,3Topical application of piericidin B (4 μg/insect) induces mortality in 87.5% of houseflies (M. domestica).1It induces 93.3, 100, and 100% mortality in rice stem borer (C. simples), silkworm (B. mori), and green caterpillar (P. rapae) larvae, respectively, when applied at respective concentrations of 60, 4.8, and 96 μg/larva. Piericidin B is active against the fungiT. asteroides,T. rubrum,M. gypseum, andC. neoforms(MICs = 20, 10, 20, and 2 μg/ml, respectively), as well as the bacteriaM. luteusandP. vulgaris(MICs = 50 and 100 μg/ml, respectively). 1.Takahashi, N., Suzuki, A., Kimura, Y., et al.Isolation, structure and physiological activities of piericidin B, natural Insecticide produced by a StreptomycesAgr. Biol. Chem.32(9)1115-1122(1968) 2.Jeng, M., Hall, C., Crane, F.L., et al.Inhibition of mitochondrial electron transport by piericidin A and related compoundsBiochemistry7(4)1311-1322(1968) 3.Mitsui, T., Fukami, J.-I., Fukunaga, K., et al.Studies on piericidin. I. : Effects of piericidin A and B on mitochondrial electron transport in insect muscle comparing with rotenoneSci. Insect Control34(3)126-134(1969)

Carbazomycin D is a bacterial metabolite that has been found inStreptomycesand has diverse biological activities.1,2It is active against the fungiT. asteroidesandT. mentagrophytes(MIC = 100 μg/ml for both) and the bacteriumM. tuberculosis(IC50= 25 μg/ml). Carbazomycin D is cytotoxic to MCF-7, KB, NCI H187, and Vero cells (IC50s = 21.3, 33.2, 12.9, and 34.3 μg/ml, respectively).2 1.Naid, T., Kitahara, T., Kaneda, M., et al.Carbazomycins C, D, E and F, minor components of the carbazomycin complexJ. Antibiot. (Tokyo)40(2)157-164(1987) 2.Intaraudom, C., Rachtawee, P., Suvannakad, R., et al.Antimalarial and antituberculosis substances from Streptomyces sp. BCC26924Tetrahedron67(39)7593-7597(2011)

S1PL-IN-31 is a dual-function chemical compound acting as an inhibitor of sphingosine-1-phosphate (S1P) lyase with an IC50 value of 210 nM and as an antagonist of the Smoothened (Smo) receptor with an IC50 of 440 nM. Demonstrating therapeutic potential, this compound, at a dosage of 2 mg/kg per day, effectively mitigates cervical and thoracic lymphocyte infiltration and neuromuscular weakness in rats suffering from experimental autoimmune encephalomyelitis (EAE), a condition triggered by the MOG29-152 peptide from myelin oligodendrocyte glycoprotein. Additionally, it significantly decreases the total lymphocyte count, including reductions in subsets of CD4+ T cells, CD8+ T cells, and B cells. At a higher dosage of 100 mg/kg, S1PL-IN-31 elevates S1P levels within the heart and lymph nodes, while doses of 3 and 10 mg/kg per day notably lower heart rates in female rats, showcasing its multifaceted biological impacts and potential for clinical application.

Plipastatin A1, a lipopeptide isolated from B. cereus, demonstrates enzyme inhibitory and immunosuppressant properties. It effectively inhibits enzymes phospholipase A2 (PLA2), phospholipase C (PLC), and phospholipase D (PLD) with half-maximal inhibitory concentrations (IC50s) of 2.9, 1.3, and 1.4 µM, respectively. Additionally, at a concentration of 100 µg/ml, plipastatin A1 inhibits lipopolysaccharide (LPS)-induced B cell blastogenesis and T cell blastogenesis triggered by concanavalin A. In vivo studies reveal that a dose of 0.1 mg/animal effectively suppresses delayed-type hypersensitivity in mice.

CXCR3 antagonist 6c is an antagonist of chemokine (C-X-C motif) receptor 3 (CXCR3).1It inhibits calcium mobilization induced by chemokine (C-X-C motif) ligand 11 (CXCL11) in HEK293 cells expressing the human receptor (IC50= 0.06 μM). It is selective for CXCR3 over a panel of 14 human G protein-coupled receptors at 10 μM. CXCR3 antagonist 6c inhibits CXCR3-mediated migration of isolated human T cells (IC50= ~100 nM). 1.Cole, A.G., Stroke, I.L., Brescia, M.-R., et al.Identification and initial evaluation of 4-N-aryl-[1,4]diazepane ureas as potent CXCR3 antagonistsBioorg. Med. Chem. Lett.16(1)200-203(2006)

(-)-Mycousnine is a microbial metabolite and derivative of usnic acid originally isolated fromM. nawaethat has antibacterial and antifungal activities.1,2It is active against the Gram-positive bacteriaB. subtilis,K. rhizophila, andS. aureus(MICs = 4, 8, and 4 g/ml, respectively) but not the Gram-negative bacteriaE. coli,S. typhimurium, andK. pneumoniae(MICs = >128 g/ml for all).2(-)-Mycousnine is also active against the fungiT. mentagrophytes,T. rubrum, andC. albicans(MICs = 25, 25, and 100 μg/ml, respectively).1 1.Sassa, T., and Igarashi, M.Structures of (-)-mycousnine, (+)-isomycousnine and (+)-oxymycousnine, new usnic acid derivatives from phytopathogenic Mycosphaerella nawaeAgric. BioI. Chem.54(9)2231-2237(1990) 2.Lee, J., Lee, J., Kim, G.J., et al.Mycousfurans A and B, antibacterial usnic acid congeners from the fungus Mycosphaerella sp., isolated from a marine sedimentMar. Drugs17(7)422(2019)

TTA-A2 is a selective T-type calcium channel antagonist as a potent anticonvulsant that the Cav3.1 isoform plays a prominent role in mediating. TTA-A2 is equally potent against the Cav3.1 (a1G) and Cav3.2 (a1H) channels with IC50 values of 89 nM and 92 nM, respectively, at -80 and -100 mV holding potentials. TTA-A2 can be used for the research of a variety of human neurological diseases, including sleep disorders and epilepsy.

S-72 acts as a microtubule polymerization inhibitor, effective in cell-free assays at concentrations of 1, 3, and 10 µM. At nanomolar levels (IC50s = 15.64 and 26.32 nM, respectively), it diminishes the viability of both MCF-7 and paclitaxel-resistant MCF-7/T breast cancer cells. Moreover, at 50 nM, S-72 impedes migration, invasion, and wound healing in these cell lines. Additionally, at 100 nM, it arrests the cell cycle at the G2/M phase and induces apoptosis in MCF-7/T cells, while also inhibiting stimulator of interferon genes (STING) activation. In vivo, S-72 dosage at 15 mg/kg per day curtails tumor growth in mouse xenograft models of paclitaxel-resistant breast cancer, specifically MCF-7/T and MX-1/T.

NG 25 is a type II kinase inhibitor that inhibits MAP4K2 and TAK1 (IC50s = 21.7 and 149 nM, respectively).1It also inhibits the Src family kinases Src and LYN (IC50s = 113 and 12.9 nM, respectively) and Abl family kinases (IC50s = 75.2 nM), as well as CSK, FER, and p38α (IC50s = 56.4, 82.3, and 102 nM, respectively). NG 25 (100 nM) prevents TNF-α-induced IKKα/β phosphorylation and IκB-α degradation in L929 cells. It inhibits secretion of IFN-α and IFN-β induced by CpG type B and CL097, respectively, in Gen2.2 cells in a concentration-dependent manner.2NG 25 decreases cell viability of HCT116KRASWT, and to a greater degree of HCT116KRASG13D, colorectal cancer cells in a concentration-dependent manner.3It also reduces tumor growth and increases the number of TUNEL-positive tumor cells in a CT26KRASG12Dmouse orthotopic model of colorectal cancer. 1.Tan, L., Nomanbhoy, T., Gurbani, D., et al.Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)J. Med. Chem.58(1)183-196(2015) 2.Pauls, E., Shpiro, N., Peggie, M., et al.Essential role for IKKβ in production of type 1 interferons by plasmacytoid dendritic cellsJ. Biol. Chem. 287(23)19216-19228(2012) 3.Ma, Q., Gu, L., Liao, S., et al.NG25, a novel inhibitor of TAK1, suppresses KRAS-mutant colorectal cancer growth in vitro and in vivoApoptosis24(1-2)83-94(2019)

Urocortin III is a neuropeptide hormone and member of the corticotropin-releasing factor (CRF) family which includes mammalian CRF , urocortin , urocortin II , frog sauvagine, and piscine urotensin I.1 Human urocortin III shares 90, 40, 37, and 21% identity to mouse urocortin III , mouse urocortin II , human urocortin , and mouse urocortin, respectively. Urocortin III selectively binds to type 2 CRF receptors (Kis = 21.7, 13.5, and >100 nM for rat CRF2α, rat CRF2β, and human CRF1, respectively). It stimulates cAMP production in CHO cells expressing rat CRF2α and mouse CRF2β (EC50s = 0.16 and 0.12 nM, respectively) as well as cultured anterior pituitary cells expressing endogenous CRF2β. Urocortin III is co-released with insulin to potentiate glucose-stimulated somatostatin release in vitro in human pancreatic β-cells.2 In vivo, urocortin III reduces food intake in a dose- and time-dependent manner in mice with a minimum effective dose (MED) of 0.3 nmol/animal.3 It increases swimming time in a forced swim test in mice, indicating antidepressant-like activity.4References1. Lewis, K., Li, C., Perrin, M.H., et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc. Natl. Acad. Sci. U.S.A. 98(13), 7570-7575 (2001).2. van der Meulen, T., Donaldson, C.J., Cáceres, E., et al. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat. Med. 21(7), 769-776 (2015).3. Pelleymounter, M.A., Joppa, M., Ling, N., et al. Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III. Peptides 25(4), 659-666 (2004).4. Tanaka, M., Kádár, K., Tóth, G., et al. Antidepressant-like effects of urocortin 3 fragments. Brain Res. Bull. 84(6), 414-418 (2011). Urocortin III is a neuropeptide hormone and member of the corticotropin-releasing factor (CRF) family which includes mammalian CRF , urocortin , urocortin II , frog sauvagine, and piscine urotensin I.1 Human urocortin III shares 90, 40, 37, and 21% identity to mouse urocortin III , mouse urocortin II , human urocortin , and mouse urocortin, respectively. Urocortin III selectively binds to type 2 CRF receptors (Kis = 21.7, 13.5, and >100 nM for rat CRF2α, rat CRF2β, and human CRF1, respectively). It stimulates cAMP production in CHO cells expressing rat CRF2α and mouse CRF2β (EC50s = 0.16 and 0.12 nM, respectively) as well as cultured anterior pituitary cells expressing endogenous CRF2β. Urocortin III is co-released with insulin to potentiate glucose-stimulated somatostatin release in vitro in human pancreatic β-cells.2 In vivo, urocortin III reduces food intake in a dose- and time-dependent manner in mice with a minimum effective dose (MED) of 0.3 nmol/animal.3 It increases swimming time in a forced swim test in mice, indicating antidepressant-like activity.4 References1. Lewis, K., Li, C., Perrin, M.H., et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc. Natl. Acad. Sci. U.S.A. 98(13), 7570-7575 (2001).2. van der Meulen, T., Donaldson, C.J., Cáceres, E., et al. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat. Med. 21(7), 769-776 (2015).3. Pelleymounter, M.A., Joppa, M., Ling, N., et al. Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III. Peptides 25(4), 659-666 (2004).4. Tanaka, M., Kádár, K., Tóth, G., et al. Antidepressant-like effects of urocortin 3 fragments. Brain Res. Bull. 84(6), 414-418 (2011).

Palmitoylcholine is an acyl choline.1It inhibits protein kinase C activity when used at a concentration of 100 μM.2Palmitoylcholine induces hemolysis in rat erythrocytes.3Plasma levels of palmitoylcholine are decreased in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).1 1.Germain, A., Barupal, D.K., Levine, S.M., et al.Comprehensive circulatory metabolomics in ME/CFS reveals disrupted metabolism of acyl lipids and steroidsMetabolites10(1)34(2020) 2.Nakadate, T., and Blumberg, P.M.Modulation by palmitoylcarnitine of protein kinase C activationCancer Res.47(24 Pt 1)6537-6542(1987) 3.Cho, K.S., and Proulx, P.Interactions of acyl carnitines and other lysins with erythrocytes and reconstituted erythrocyte lipoproteinsBiochim. Biophys. Acta318(1)50-60(1973)

KRN2 has potential to treat NFAT5-mediated Chronic Arthritis. KRN2 is a selective inhibitor of nuclear factor of activated T cells (NFAT5), with an IC50 of 100 nM.

KUS121 is a valosin-containing protein (VCP) modulator that inhibits VCP ATPase activity (IC50= 330 nM).1It inhibits cell death, ATP depletion, and upregulation of C/EBP-homologous protein (CHOP) induced by tunicamycin, an inducer of ER stress, in HeLa cells when used at concentrations of 20, 50, and 50 μM, respectively. KUS121 (100 μM) inhibits ATP depletion and cell death induced by oxygen-glucose deprivation (OGD) in rat primary cortical neurons in anin vitromodel of cerebral ischemia.2It reduces infarction volume and increases the latency to fall in an accelerating rotarod test in a mouse model of focal cerebral ischemia induced by transient distal middle cerebral artery occlusion (MCAO) when administered at a dose of 100 mg/kg immediately following occlusion and again at 50 mg/kg following reperfusion. KUS121 (50 mg/kg) inhibits thinning of the retinal outer nuclear layer and preserves visual function in an rd10 mouse model of retinitis pigmentosa.1 1.Ikeda, H.O., Sasaoka, N., Koike, M., et al.Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosaSci. Rep.45970(2014) 2.Kinoshita, H., Maki, T., Yasuda, K., et al.KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletionSci. Rep.9(1)11519(2019)

MK-3207 is a potent and orally bioavailable CGRP receptor antagonist (IC 50 = 0.12 nM; K i = 0.024 nM); highly selective versus human AM1, AM2, CTR, and AMY3. IC50 Value: 0.024 nM (Ki, Human CGRP) [1] As other CGRP receptor antagonists, MK-3207 shows a lower affinity for human CGRP receptors from other species, including canine and rodent. in vitro: MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). in vivo: MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min [1]. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage [2]. Clinical trial: MK-3207 for the treatment of acute migraines. Phase 2b

CC-90005 is a potent, selective and orally active inhibitor of protein kinase C-θ (PKC-θ), with an IC50 of 8 nM. CC-90005 shows selectivity for PKC-θ over PKC-δ (IC50=4440 nM). CC-90005 can inhibit T cell activation by IL-2 expression[1]. CC-90005 shows the exquisite selectivity of CC-90005, with IC50s for all other family members of >3 μM[1].CC-90005 is a moderate inhibitor of both CYP2C9 (IC50=8 μM) and CYP2C19 (IC50=5.9 μM) in human liver microsomes[1].CC-90005 inhibits IL-2 expression in LRS_WBC human PBMCs, with an IC50 of 0.15 μM[1].CC-90005 (1-10 μM; 24 h) inhibits T cell proliferation in PBMCs by 51% at 1 μM and 88% at 3 μM[1]. CC-90005 (3-30 mg/kg; p.o. twice daily for 4 days) significantly reduces the popliteal lymph node (PLN) size in a model of chronic T cell activation[1].CC-90005 (100 mg/kg; a single p.o.) significantly inhibits plasma and spleen IL-2 release by 51 and 54%, respectively[1].CC-90005 exhibits reasonable oral bioavailability (66 and 46%) and Cmax (1.18 and 1.2 μM) following oral administration (10 and 3 mg/kg) in rat and dog, respectively[1].CC-90005 exhibits the mean residence time (0.52 and 2.0 h), CL (69.1 and 20.5 mL/min/kg) and Vss (2.11 and 2.44 L/kg) following intravenous administration (2 and 1 mg/kg) in rat and dog, respectively[1]. [1]. Papa P, et, al. Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005. J Med Chem. 2021 Aug 26;64(16):11886-11903.

2-(1-(Thiophen-2-yl)ethylidene)hydrazinecarbothioamide is an antimicrobial agent.1It is active against the Gram-negative bacteriaE. coli,P. aeruginosa, andS. marcescens(MICs = 64, 100, and 70 μg/ml, respectively), the Gram-positive bacteriaS. aureus,M. luteus, andB. cereus(MICs = 130, 100, and 50 μg/ml, respectively), and the fungiC. albicans,G. candidum,T. rubrum,F. oxysporum,A. flavus, andS. brevicaulis(MICs = 69-120 μg/ml). 2-(1-(Thiophen-2-yl)ethylidene)hydrazinecarbothioamide is also a precursor in the synthesis of other antimicrobial agents, as well as compounds with anticancer activity.1,2 1.Youssef, M.S.K., and Abeed, A.A.O.Synthesis and antimicrobial activity of some novel 2-thienyl substituted heterocyclesHeterocycl. Commun.20(1)25-31(2014) 2.Gomha, S.M., Edrees, M.M., and Altalbawy, F.M.A.Synthesis and characterization of some new bis-pyrazolyl-thiazoles incorporating the thiophene moiety as potent anti-tumor agentsInt. J. Mol. Sci.17(9)1499(2016)

2,5-dimethyl Celecoxib is a derivative of celecoxib that does not inhibit COX-2 (IC50 = >100 μM).1 It does inhibit microsomal prostaglandin E synthase-1 (mPGES-1) in HeLa cells (IC50 = 15.6 μM) and reduces prostaglandin E2 production in HeLa, A549, and HCA-7 cells (IC50s = 0.64, 0.83, and 3.08 μM, respectively).2 It inhibits proliferation of drug-sensitive RPMI8226 and multidrug-resistant 8226/Dox40 multiple myeloma cells, as well as increases the rate of apoptosis when used at concentrations of 20 and 30 μM.3 2,5-dimethyl Celecoxib reduces the expression of survivin, cyclin A, cyclin B, MEK1, and MEK2 in 8226/Dox40 cells. The antiproliferative effect of 2,5-dimethyl celecoxib is independent of mPGES-1 inhibition.2References1. Zhu, J., Song, X., Lin, H.-P., et al. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J. Natl. Cancer Inst. 94(23), 1745-1757 (2002).2. Wobst, I., Schiffmann, S., Birod, K., et al. Dimethylcelecoxib inhibits prostaglandin E2 production. Biochem. Pharmacol. 76(1), 62-69 (2008).3. Kardosh, A., Soriano, N., Liu, Y.-T., et al. Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib. Blood 106(13), 4330-4338 (2005). 2,5-dimethyl Celecoxib is a derivative of celecoxib that does not inhibit COX-2 (IC50 = >100 μM).1 It does inhibit microsomal prostaglandin E synthase-1 (mPGES-1) in HeLa cells (IC50 = 15.6 μM) and reduces prostaglandin E2 production in HeLa, A549, and HCA-7 cells (IC50s = 0.64, 0.83, and 3.08 μM, respectively).2 It inhibits proliferation of drug-sensitive RPMI8226 and multidrug-resistant 8226/Dox40 multiple myeloma cells, as well as increases the rate of apoptosis when used at concentrations of 20 and 30 μM.3 2,5-dimethyl Celecoxib reduces the expression of survivin, cyclin A, cyclin B, MEK1, and MEK2 in 8226/Dox40 cells. The antiproliferative effect of 2,5-dimethyl celecoxib is independent of mPGES-1 inhibition.2 References1. Zhu, J., Song, X., Lin, H.-P., et al. Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. J. Natl. Cancer Inst. 94(23), 1745-1757 (2002).2. Wobst, I., Schiffmann, S., Birod, K., et al. Dimethylcelecoxib inhibits prostaglandin E2 production. Biochem. Pharmacol. 76(1), 62-69 (2008).3. Kardosh, A., Soriano, N., Liu, Y.-T., et al. Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib. Blood 106(13), 4330-4338 (2005).

Pestalotin is a fungal metabolite originally isolated from P. cryptomeriaecola with diverse biological activities. It induces reducing sugar release in embryoless rice endosperms when used at concentrations ranging from 3 to 100 mg L and enhances growth of rice seedlings (O. sativa) when used in combination with gibberellin A3 at concentrations ranging from 30 to 500 mg L. Pestalotin has antifungal activity, reducing the growth of C. albicans, C. neoformans, T. rubrum, and A. fumigatus (MICs = 12.5, 50, 50, and 50 μg ml, respectively). It is cytotoxic to HL-60, MKN45, LoVo, and A549 cells (IC50s = 64.87-182.92 μM). Pestalotin has been used as a standard for dereplication of natural products.

Terpendole I is a fungal metabolite that has been found in A. yamanashiensis.1 It is a weak inhibitor of acyl-coenzyme A:cholesterol acyltransferase (ACAT; IC50 = 145 μM) and is active against the bacteria B. cereus and B. subtilis (MICs = 100 μg/ml for both) but not S. aureus, P. aeruginosa, or K. pneumoniae (MICs = >200 μg/ml for all) or the fungus C. albicans (MIC = 200 μg/ml).1,2 It is cytotoxic to HeLa cells with an IC50 value of 52.6 μM.3 |1. Tomoda, H., Tabata, N., Yang, D.-J., et al. Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. III. Production, isolation and structure elucidation of new components. J. Antibiot. (Tokyo) 48(8), 793-804 (1995).|2. Zhao, J.-C., Wang, Y.-L., Zhang, T.-Y., et al. Indole diterpenoids from the endophytic fungus Drechmeria sp. as natural antimicrobial agents. Phytochemistry 148, 21-28 (2018).|3. Nagumo, Y., Motoyama, T., Hayashi, T., et al. Structure-activity relationships of terpendole E and its natural derivatives. ChemistrySelect 2(4), 1533-1536 (2017).

Roccellic acid is a lichen secondary metabolite that has been found in R. montagnei and has antibacterial and anticancer activities.1,2 It is active against the bacteria S. gordonii and P. gingivalis (MIC = 46.9 μg/ml for both).1 Roccellic acid (100 μg/ml) inhibits proliferation of MDA-MB-231, MCF-7, and DLD-1 cancer cells by 65.3, 75.8, and 87.9%, respectively.2 |1. Sweidan, A., Chollet-Krugler, M., Sauvager, A., et al. Antibacterial activities of natural lichen compounds against Streptococcus gordonii and Porphyromonas gingivalis. Fitoterapia 121, 164-169 (2017).|2. Mishra, T., Shukla, S., Meena, S., et al. Isolation and identification of cytotoxic compounds from a fruticose lichen Roccella montagnei, and it's in silico docking study against CDK-10. Rev. Bras. Farmacogn. 27(6), 724-728 (2017).

Methylspinazarin is a naphthoquinone bacterial metabolite that has been found in Streptomyces and is an inhibitor of catechol O-methyltransferase (COMT; IC50 = 0.8 μg/ml).1 It is selective for COMT over tyrosine hydroxylase, DOPA decarboxylase, and dopamine-β-hydroxylase at 100 μg/ml. Methylspinazarin decreases blood pressure in spontaneously hypertensive rats when administered at a dose of 50 mg/kg. |1. Chimura, H., Sawa, T., Takita, T., et al. Methylspinazarin and dihydromethylspinazarin, gatechol-O-methyl transerfase inhibitors produced by Streptomyces. J. Antibiot. 26(2), 112-114 (1973).

Tetranactin is a macrotetrolide and a monovalent cation ionophore that has been found in S. aureus and has antibacterial, insecticidal, and mitogenic activities. It exhibits an equilibrium permeability ratio 1,000-fold greater for lithium than sodium or cesium ions accross bilayer membranes at low voltages. Tetranactin inhibits the growth of Gram-positive bacteria and C. miyabeanus and R. solani fungi when used at concentrations less than 0.9 μg/ml. Tetranactin (0.5-1.5 μg per insect) dose-dependently increases the mortality of adult C. chinensis weevils up to 100% and has mitogenic activity against T. telarius when sprayed onto plants with an LC50 value of 9.2 μg/ml. It reduces IL-1β- and cAMP-induced secretion of phospholipase A2 (PLA2) from rat mesangial cells (IC50s = 43 and 33 nM, respectively). Tetranactin (50 ng/ml) suppresses the proliferation of human T lymphocytes induced by allogeneic cells and IL-2 and supresses the generation of cytotoxic T lymphocytes in mixed lymphocyte cultures. In vivo, tetranactin (10 mg/animal per day) completely inhibits the formation of experimental autoimmune uveoretinitis (EAU) in rats.

Ara-G is an analog of the nucleoside guanosine and an active metabolite of nelarabine .1,2 Ara-G accumulates in T lymphoblasts and malignant T-lymphoid cells, where it is phosphorylated to produce ara-GTP and incorporated into the DNA.3,1 Ara-G inhibits DNA replication by 92% after 30 minutes when used at a concentration of 50 μM in CEM cells, which are used as a model for human T lymphoblasts.1 It also halts the cell cycle at the sub-G1 phase and induces apoptosis in CEM cells.3 Syngeneic bone marrow containing 6C3HED tumor cells treated with ara-G (100 mM) ex vivo prior to transplantation increases survival of lethally irradiated mice and induces reconstitution of lymphoid, myeloid, and erythroid cell linages.4References1. Leanza, L., Miazzi, C., Ferraro, P., et al. Activation of guanine-β-D-arabinofuranoside and deoxyguanosine to triphosphates by a common pathway blocks T lymphoblasts at different checkpoints. Exp. Cell Res. 316(20), 3443-3453 (2010).2. Lambe, C.U., Averett, D.R., Paff, M.T., et al. 2-Amino-6-methoxypurine arabinoside: An agent for T-cell malignancies. Cancer Res. 55(15), 3352-3356 (1995).3. Rodriguez, C.O., Jr., Stellrecht, C.M., and Gandhi, V. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood 102(5), 1842-1848 (2003).4. Kurtzberg, J. Guanine arabinoside as a bone marrow-purging agent. Ann. N.Y. Acad. Sci 685(1), 225-236 (1993). Ara-G is an analog of the nucleoside guanosine and an active metabolite of nelarabine .1,2 Ara-G accumulates in T lymphoblasts and malignant T-lymphoid cells, where it is phosphorylated to produce ara-GTP and incorporated into the DNA.3,1 Ara-G inhibits DNA replication by 92% after 30 minutes when used at a concentration of 50 μM in CEM cells, which are used as a model for human T lymphoblasts.1 It also halts the cell cycle at the sub-G1 phase and induces apoptosis in CEM cells.3 Syngeneic bone marrow containing 6C3HED tumor cells treated with ara-G (100 mM) ex vivo prior to transplantation increases survival of lethally irradiated mice and induces reconstitution of lymphoid, myeloid, and erythroid cell linages.4 References1. Leanza, L., Miazzi, C., Ferraro, P., et al. Activation of guanine-β-D-arabinofuranoside and deoxyguanosine to triphosphates by a common pathway blocks T lymphoblasts at different checkpoints. Exp. Cell Res. 316(20), 3443-3453 (2010).2. Lambe, C.U., Averett, D.R., Paff, M.T., et al. 2-Amino-6-methoxypurine arabinoside: An agent for T-cell malignancies. Cancer Res. 55(15), 3352-3356 (1995).3. Rodriguez, C.O., Jr., Stellrecht, C.M., and Gandhi, V. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood 102(5), 1842-1848 (2003).4. Kurtzberg, J. Guanine arabinoside as a bone marrow-purging agent. Ann. N.Y. Acad. Sci 685(1), 225-236 (1993).

Cbl-b-IN-13 (Example 520) is a potent Cbl-b inhibitor exhibiting an IC50 of less than 100 nM and is capable of activating T-cells [1].

AKP-11 is a sphingosine-1-phosphate receptor 1 (S1P1) agonist with an EC50 of 0.047 μM for [35S]GTPγS binding to CHO-K1 cell membranes expressing human S1P1. It reduces S1P1 surface expression and enhances Akt and ERK phosphorylation in CHO cells with S1P1-HA at a 100 nM concentration. At doses of 1.3 and 3 mg/kg, AKP-11 lowers IFN-γ and IL-17 protein levels in the spinal cord and mitigates disease severity in a rat experimental autoimmune encephalomyelitis (EAE) model. Additionally, it decreases peripheral total lymphocyte and specific T cell subsets (CD4+, CD8+, and CD26L+ T cells) counts in both EAE rats and healthy controls at a 1.3 mg/kg dosage.

Oosporein is a mycotoxin that has been found inBeauveriaand has diverse biological activities.1,2It is cytotoxic to Sf9 and Sf21 insect cells with 50% cytotoxic concentration (CC50) values of 4.23 and 10.43 μM, respectively.3Oosporin induces lethality in day-old cockerels (LD50= 6.12 mg/kg).4It inhibits Na+/K+-, Ca2+-, and Mg2+-ATPase activities by 27, 52, and 100%, respectively, in equine erythrocyte ghosts when used at a concentration of 200 μg/ml.2Oosporein inhibits herpes simplex 1 (HSV-1), but not HeLa cell orE. coli, DNA polymerase (IC50s = 75, 610, and >700 μM, respectively).5It is active against the bacteriumS. pneumoniae(MIC = 32 μg/ml) and the plant pathogenic fungusP. infestans(MIC = 16 μM).1,6 1.Wainwright, M., Betts, R.P., and Teale, D.M.Antibiotic activity of oosporein from Verticillium psalliotaeTrans. Br. Mycol. Soc.86(1)168-170(1986) 2.Jeffs, L.B., and Khachatourians, G.G.Toxic properties of Beauveria pigments on erythrocyte membranesToxicon. 35(8)1351-1356(1997) 3.Arboleda Valencia, J.W., Gaitán Bustamante, A.L., Jiménez, A.V., et al.Cytotoxic activity of fungal metabolites from the pathogenic fungus Beauveria bassiana: An intraspecific evaluation of beauvericin productionCurr. Microbiol.63(3)306-312(2011) 4.Cole, R.J., Kirksey, J.W., Cutler, H.G., et al.Toxic effects of oosporein from Chaetomium trilateraleJ. Agric. Food Chem.22(3)517-520(1974) 5.Terry, B.J., Liu, W.C., Cianci, C.W., et al.Inhibition of herpes simplex virus type 1 DNA polymerase by the natural product oosporeinJ. Antibiot. (Tokyo)45(2)286-288(1992) 6.Nagaoka, T., Nakata, K., Kouno, K., et al.Antifungal activity of oosporein from an antagonistic fungus against Phytophthora infestansZ. Naturforsch. C. J. Biosci.59(3-4)302-304(2004)

Pyridaben is a METI acaricide that inhibits mitochondrial electron transport at complex I (METI; Ki = 0.36 nmol/mg protein in rat brain mitochondria).

PTP1B-IN-21 is a compound that functions as a selective inhibitor of protein tyrosine phosphatase 1B (PTP1B; IC50=1.56 μM), demonstrating a marked preference over the structurally similar T-cell protein tyrosine phosphatase (TCPTP; IC50>100 μM). This specificity highlights its potential as a critical agent for type 2 diabetes management.

Epoxomicin (BU-4061T,Aids010837) is a selective proteasome inhibitor with anti-inflammatory activity, inhibits primarily the CH-L activity of the 20S proteasome, while T-L and PGPH catalytic activities are also inhibited at 100- and 1000-fold reduced rate.