δ 1

PPARα δ agonist 1 is a potent dual agonist with EC50 values of 7.0 nM for PPARα and 8.4 nM for PPARδ, exhibiting high selectivity for PPARγ (EC50: 1316.1 nM). Agonist 1 has potential for non-alcoholic steatohepatitis studies.

6-Deoxy-3-O-methyl-β-allopyranosyl (1→4)-β-cymaronic acid δ-lactone is a natural product from Marsdenia tenacissima

δ-Tocotrienolprodrug-1 (compound 5b) serves as a prodrug of δ-tocotrienol. This compound possesses radioprotective properties and aids in the regeneration of hematopoietic progenitor and stem cells in the bone marrow and spleen of mice.

Resveratrol (SRT 501) is a polyphenolic natural product, a plant antitoxin with antioxidant and chemopreventive activities. Resveratrol has a wide range of targets including COX, SIRT, LOC, etc. Resveratrol induces autophagy and apoptosis.

Eicosapentaenoic Acid is an ω-3 fatty acid and an inhibitor of fatty acid synthase (FASN). Eicosapentaenoic Acid promotes DNA demethylation in the reexpression of the tumor suppressor gene CCAAT/ enhancer-binding protein δ (C/EBPδ). Eicosapentaenoic Acid activates the RAS/ERK/C/EBPβ pathway in U937 leukemia cells through demethylation of the CpG island of H-RAS intron 1. Eicosapentaenoic Acid promotes the relaxation of vascular smooth muscle cells and vasodilation.

Hemin (Hemin chloride) is a chlorinated iron-containing porphyrin, a heme oxygenase (HO)-1 inducer. Hemin has therapeutic activity in porphyrias by reducing heme deficiency in patients, thereby inhibiting δ-aminolevulinic acid synthetase activity through biochemical feedback.

GW 501516 (Endurobol) is a effective and highly specifc PPARβ/δ agonist (EC50: 1 nM), with 1000-fold selectivity over hPPARα/γ.

β-Endorphin (1-27) (human) acetate, existing in the hypophysis cerebri and hypothalamus, exhibits antinociception activity. β-Endorphin (1-27) (human) acetate is an agonist of opioid receptor, showing preferred affinity for μ-opioid receptor and δ-opioid

AMG-548 is a selective and orally active p38α MAPK inhibitor (Ki = 0.5 nM), with higher selectivity than p38β, p38γ, and p38δ, and can also inhibit the TNFα, CK1δ/ε, and Wnt signalling pathways.

Pparδ agonist 1 is an agonist of PPAR-δ(EC50 of 5.06 nM).

AMG 511 is a potent and orally available pan inhibitor of class I PI3Ks (Kis of 4 nM, 6 nM, 2 nM, and 1 nM for PI3Kα, β, δ, and γ, respectively), exhibiting anti-tumor activity in a mouse glioblastoma xenograft model[1]. AMG 511 significantly suppresses PI3K signaling as indicated by a decrease in p-Akt (Ser473).

Aphidicolin, an antibiotic derived from the mold Cephalosporium aphidicola, is a potent inhibitor of DNA (deoxyribonucleic acid) synthesis, effectively hindering the proliferation of herpes simplex virus[2]. It targets DNA polymerase α and δ, disrupting mitotic cell division by affecting DNA polymerase activity[1]. Additionally, aphidicolin enhances apoptosis when combined with arabinosyl nucleosides in a human promyelocytic leukemia cell line[3].

BAY1082439, an orally bioavailable, selective inhibitor of PI3Kα β δ, demonstrates high efficacy in inhibiting the growth of Pten-null prostate cancer [1][2]. Additionally, BAY1082439 is effective against mutated forms of PIK3CA.

MOR modulator-1 (compound 6) is a potent and selective modulator of the μ opioid receptor (MOR). Compared to NAT (6α-configuration), MOR modulator-1 demonstrates improved opioid receptor selectivity, enhanced antagonistic effects in vivo, and overall reduced withdrawal symptoms. It connects to the μ, δ, and γ receptors with carboxamide linkers, showing Ki values of 0.25, 41.1, and 1.30 nM respectively.

JD123 inhibits the activity of JNK1 and the expression of cJun (1-135). It is an ATP-competitive inhibitor specific to p38-γ MAPK and has no effect on ERK1, ERK2, p38-α, p38-β, and p38-δ.

PPAR agonist6 (compound 5a) acts as an agonist for PPAR, exhibiting EC50 values of 3.6 μM and 2.6 μM for PPARα and PPARβ/δ respectively. Additionally, PPAR agonist6 inhibits the transactivation of a TNFα-dependent NF-κB-driven reporter gene in L929 cells [1].

PI3K/HDAC-IN-4 (Compound 31f) is a dual inhibitor targeting PI3K and HDAC, with an IC50 of 0.2μM. It demonstrates high selectivity for HDAC1-3, with IC50 values of 75.5 nM, 70.9 nM, and 1.9 nM, respectively. As a potent pan-PI3K inhibitor, PI3K/HDAC-IN-4 has IC50 values of 2.5 nM, 80.5 nM, 10.0 nM, and 57.2 nM for PI3Kα, β, δ, and γ, respectively. This compound effectively induces apoptosis in tumor cells by concurrently inhibiting the PI3K/AKT/mTOR signaling pathway and HDAC1-3. It shows significant antiproliferative activity across various tumor cell lines, such as MV4-11, Jeko-1, HL60, and MCF-7, with IC50 values of 0.2, 0.9, 0.8, and 1.5 μM, respectively. PI3K/HDAC-IN-4 is applicable in the study of lymphoma and leukemia.

BW373U86 (SNC86), a δ-opioid receptor agonist, demonstrates potent activity with an IC50 value of 1.49 nM and has shown to exhibit antidepressant-like effects [1].

Alvimopan dihydrate (ADL 8-2698 dihydrate) is a potent, selective, orally active, and reversible μ-opioid receptor antagonist with an IC50 of 1.7 nM. Highly selective for the μ-opioid receptor (Ki = 0.47 nM) over κ- and δ-opioid receptors (Kis = 100 and 12 nM, respectively), Alvimopan dihydrate can be used for research on postoperative ileus [1] [2] [3].

PI3Kα-IN-4 is a potent, selective, and orally active PI3Kα inhibitor with an IC50 of 1.8 nM, demonstrating antitumor activity [1].

T2AA (4-[4-[(2S)-2-amino-3-hydroxypropyl]-2,6-diiodophenoxy]phenol) is an inhibitor of proliferating cell nuclear antigen (PCNA) with IC50 of 1 μM for PCNA PIP-box peptide interaction. T2AA suppresses cancer cell growth and causes DNA replication stress by stalling DNA replication forks and inhibiting PCNA interaction with DNA polymerase δ.

MBX-8025 is an agonist of peroxisome proliferator-activated receptor δ (PPARδ).1 It is greater than 750- and 2,500-fold selective for PPARδ over PPARα and PPARγ. MBX-8025 (10 mg/kg per day for eight weeks) reduces increases in fasting blood glucose and serum insulin levels, and decreases insulin resistance in Alms1 mutant (foz/foz) mice fed an atherogenic diet as a model of diet-induced obesity, type 2 diabetes, and non-alcoholic steatohepatitis (NASH).2 It also decreases serum alanine transaminase (ALT), as well as serum and hepatic cholesterol and triglyceride, levels and reduces markers of NASH in the same model. |1. Bays, H.E., Schwartz, S., Littlejohn, T., 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-δ agonist: Lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96(9), 2889-2897 (2011).|2. Haczeyni, F., Wang, H., Barn, V., et al. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol. Commun. 1(7), 663-674 (2017).

MD001 is a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and PPARγ.1 It binds to PPARα and PPARγ (Kds = 9.55 and 0.14 μM, respectively) but does not bind to PPARβ/δ at concentrations up to 500 μM. It increases transcriptional activity of PPARα and PPARγ in a cell-based luciferase reporter assay when used at a concentration of 10 μM. MD001 (10 μM) increases expression of PPARα, PPARγ, and retinoid X receptor (RXR), as well as PPARα and PPARγ target genes, in HepG2 cells. It increases glucose consumption as well as expression of GLUT2 and GLUT4 in HepG2 and 3T3-L1 cells, respectively, in a concentration-dependent manner. MD001 (20 mg/kg) decreases levels of glucose, insulin, free fatty acids, triglycerides, LDL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in blood and reduces the size and number of hepatic lipid droplets in diabetic db/db mice.References1. Kim, S.-H., Hong, S.H., Park, Y.-J., et al. MD001, a novel peroxisome proliferator-activated receptor α/γ agonist, improves glucose and lipid metabolism. Sci. Rep. 9(1), 1656 (2019). MD001 is a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and PPARγ.1 It binds to PPARα and PPARγ (Kds = 9.55 and 0.14 μM, respectively) but does not bind to PPARβ/δ at concentrations up to 500 μM. It increases transcriptional activity of PPARα and PPARγ in a cell-based luciferase reporter assay when used at a concentration of 10 μM. MD001 (10 μM) increases expression of PPARα, PPARγ, and retinoid X receptor (RXR), as well as PPARα and PPARγ target genes, in HepG2 cells. It increases glucose consumption as well as expression of GLUT2 and GLUT4 in HepG2 and 3T3-L1 cells, respectively, in a concentration-dependent manner. MD001 (20 mg/kg) decreases levels of glucose, insulin, free fatty acids, triglycerides, LDL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in blood and reduces the size and number of hepatic lipid droplets in diabetic db/db mice. References1. Kim, S.-H., Hong, S.H., Park, Y.-J., et al. MD001, a novel peroxisome proliferator-activated receptor α/γ agonist, improves glucose and lipid metabolism. Sci. Rep. 9(1), 1656 (2019).

ZLY032 is a dual agonist of free fatty acid receptor 1 (FFAR1/GPR40; EC50= 68 nM in a FLIPR assay) and peroxisome proliferator-activated receptor δ (PPARδ; EC50= 102 nM in a reporter assay).1It is selective for FFAR1 and PPARδ over PPARα and PPARγ (EC50s = >10 μM for both). ZLY032 (40 mg/kg, twice per day) reduces blood glucose levels in an oral glucose tolerance test and decreases plasma total cholesterol and triglyceride levels in theob/obmouse model of metabolic disease.2It reduces hepatic steatosis and plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a methionine and choline-deficient diet at the same dose. 1.Li, Z., Chen, Y., Zhou, Z., et al.Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agentsEur. J. Med. Chem.164352-365(2019) 2.Li, Z., Zhou, Z., Hu, L., et al.ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosisPharmacol Res.159105035(2020)