RANKL/RANK Inhibitor

Denosumab is a human monoclonal antibody that targets the protein RANKL. Denosumab binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) and prevents its binding to the RANK receptor (K_D of 0.003 nM for human RANKL). Denosumab promotes proliferation and spermatogenesis. Denosumab prevents bone resorption through inhibition of the NF-κB pathway. Denosumab can be used in bone-related studies.

Boldine is an apomorphine isoquinoline alkaloid extracted from the root of the pheasant pepper (Litsea cubeba). Boldine is an oral effective antioxidant, anti-inflammatory, antitumor agent, and can inhibit osteoclast formation. Boldine induces apoptosis of human bladder cancer cells by regulating ERK, AKT and GSK-3β. Boldine ameliorates bone destruction by down-regulating the OPG/RANKL/RANK signaling pathway. It can be used in rheumatoid arthritis research.

Anti-Mouse RANKL/CD254 Antibody (IK22/5) is an anti-mouse RANKL/CD254 IgG2a monoclonal antibody. Anti-Mouse RANKL/CD254 Antibody (IK22/5) inhibits osteoclast formation and activity by specifically blocking the binding of RANKL and RANK. Anti-Mouse RANKL/CD254 Antibody (IK22/5) can inhibit the expression of MuRF1/Trogin-1 and activation of NF-κB. Anti-Mouse RANKL/CD254 Antibody (IK22/5) can be used for research on cancer such as melanoma or colon cancer and osteoporosis.

Roburic acid acts as an anti-inflammatory, anti-tumor and osteoclastogenesis inhibitor, with a K_i of 7.066 μM against human TNF, an IC₅₀ of 9 μM against human COX-2, and an IC₅₀ of 5 μM against ovine COX-1. Roburic acid reduces the production of inflammatory mediators such as NO and IL-6 in macrophages by inhibiting the NF-κB and MAPK (p38/JNK) pathways. By competitively inhibiting the TNF-TNF-R1 interaction, Roburic acid blocks the downstream NF-κB signaling pathway, thereby inducing cell cycle arrest and apoptosis in cancer cells. Roburic acid specifically inhibits osteoclastogenesis and bone resorption by suppressing the RANKL/TRAF6/NF-κB/NFATc1 axis. Roburic acid can be used in research related to osteolytic diseases such as osteoporosis, colorectal cancer and inflammatory diseases.

Pamidronic acid, the second-generation nitrogen-containing bisphosphonate, is an inhibitor of bone loss. Pamidronic acid significantly inhibits subchondral bone loss in early osteoarthritis by upregulating the expression of OPG in cartilage and subchondral bone, and inhibiting the expression of RANKL and MMP-9 in both tissues, as well as TLR-4 in cartilage, thereby alleviating cartilage degeneration. Additionally, Pamidronic acid can inhibit the signaling of Wnt and β-catenin, and is applicable for research on osteoporosis and osteosarcoma.

Y1693 is an orally active RANKL inhibitor with a K_d of 5.03 μM for hRANKL. Y1693 inhibits the activation of the downstream c-fos/NFATc1 signaling pathway by blocking its interaction with RANK. Y1693 significantly inhibits RANKL-induced osteoclast differentiation, F-actin ring formation and bone resorptive activity, while downregulating the mRNA and protein expressions of TRAP, cathepsin K, c-fos and NFATc1. Y1693 shows no obvious cytotoxicity to bone marrow-derived macrophages and osteoclast precursor cells, and exhibits favorable ADME properties. Y1693 improves ovariectomy-induced osteoporosis in mice and reverses ligation-induced periodontal alveolar bone loss. Y1693 is applicable to research related to osteoporosis and periodontal diseases.

Cyrtominetin is a RANKL inhibitor with favorable ADMET properties. Cyrtominetin competitively blocks the binding of RANKL-RANK and increases the compactness of RANKL. Cyrtominetin can be used in studies related to osteoporosis.

E09241 is an orally active osteoclastogenesis inhibitor. E09241 reduces the RANKL-induced expression of NFATc1 and MMP-9 by activating Wnt/β-catenin. E09241 increases the OPG/RANKL ratio by upregulating OPG expression, inhibits bone resorption, promotes bone formation and prevents ovariectomy-related bone loss. E09241 can be used in the research of osteoporosis.

Isobavachin is an orally active, blood-brain barrier-penetrating prenylated flavonoid present in Psoralea corylifolia. Isobavachin inhibits human CYP2B6, CYP2C9, CYP2C19, UGT1A1, UGT1A9, and UGT2B7. Isobavachin suppresses MAPK activation, NF-κB nuclear translocation, overexpression of iNOS/COX-2, FcεRI-mediated signaling pathways, and RANKL-induced osteoclastogenesis. Isobavachin induces autophagy, cytotoxicity, neuronal differentiation, and NRF2 activation; it alleviates oxidative damage, inflammatory responses, apoptosis, iron accumulation, mitochondrial biogenesis, and mast cell degranulation. Isobavachin is applicable to research related to liver injury, inflammatory diseases, osteoporosis, liver cancer, prostate cancer, glioma, periodontitis-induced bone loss, and Alzheimer's disease.

Pamidronate disodium (CGP 23339A), the second-generation nitrogen-containing bisphosphonate, is an inhibitor of bone loss. Pamidronate disodium significantly inhibits subchondral bone loss in early osteoarthritis by upregulating the expression of osteoprotegerin in cartilage and subchondral bone, and inhibiting the expression of RANKL and MMP-9 in both tissues, as well as TLR-4 in cartilage, thereby alleviating cartilage degeneration. Additionally, Pamidronate disodium can inhibit the signaling of Wnt and β-catenin, and is applicable for research on osteoporosis and osteosarcoma.

Pamidronate disodium pentahydrate, the second-generation nitrogen-containing bisphosphonate, is an inhibitor of bone loss. Pamidronate disodium pentahydrate significantly inhibits subchondral bone loss in early osteoarthritis by upregulating the expression of osteoprotegerin in cartilage and subchondral bone, and inhibiting the expression of RANKL and MMP-9 in both tissues, as well as TLR-4 in cartilage, thereby alleviating cartilage degeneration. Additionally, Pamidronate disodium pentahydrate can inhibit the signaling of Wnt and β-catenin, and is applicable for research on osteoporosis and osteosarcoma.

2'-Acetylacteoside (2'-AA) is a natural compound with oral activity and blood-brain barrier permeability. 2'-Acetylacteosideexhibits MAO‑B inhibitory activity (IC₅₀ = 17.71 μM, K_i = 13.81 μM). 2'-Acetylacteoside downregulates the expression of RANK, TRAF6, NF‑κB, NFATc1 and IKKβ, disrupts the RANKL/RANK interaction, blocks downstream signaling pathways, and increases the level of phosphorylated Akt. 2'-Acetylacteoside possesses potent anti-osteoclastogenic, anti-bone resorptive, pro-neurogenic, neuroprotective and antioxidant activities. 2'-Acetylacteoside can be used in the research of osteoporosis, ischemic stroke and Parkinson's disease.

Rubiadin-1-methyl ether is an orally potent NF-κB p65 inhibitor and autophagy inhibitor. Rubiadin-1-methyl ether inhibits RANKL-induced phosphorylation and nuclear translocation of p65, suppresses BECN1 transcription, blocks LC3 conversion and autophagosome formation, thereby reducing the levels of BECN1 mRNA and Beclin1 protein. Rubiadin-1-methyl ether inhibits osteoclastogenesis, cell proliferation, macrophage M2 polarization and the TGF-β1 signaling pathway, and effectively alleviates pulmonary inflammation. Rubiadin-1-methyl ether is widely used in research on osteoporosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, acute lung injury and other related diseases.

WP9QY is an inhibitor targeting TNFα and RANKL, which blocks the TNFα-TNFR1 interaction and inhibits TNFα-mediated apoptosis, cytotoxicity and bone destruction. WP9QY inhibits osteoclastogenesis and promotes osteoblast differentiation, induces chondrocyte proliferation and glycosaminoglycan production, and synergizes with TGF-β3 to promote chondrogenesis. WP9QY effectively repairs full-thickness articular cartilage defects in rabbits via intra-articular injection, and inhibits methylmercury-induced reduction of NeuN-positive cells in mouse brain slices. WP9QY can be applied to the research of diseases related to methylmercury-induced neuronal death, cartilage injury, osteoarthritis and bone loss.

Necrostatin-7 (Nec-7) is a Necroptosis inhibitor with an EC₅₀ of 10.6 μM. Necrostatin-7 inhibits signal transduction from RANK to NFATc1 without affecting the activation of MAPK or NF-κB. Necrostatin-7 suppresses the expression levels of Acp5, Atp6v0d2, Ctsk and Dcstamp. Necrostatin-7 reduces myocardial infarction size, ameliorates adverse left ventricular remodeling, decreases myocardial wall stress, reduces the amount and length of scar tissue, and improves left ventricular function. Necrostatin-7 exerts cardioprotective effects in a rat model of permanent coronary artery occlusion. Necrostatin-7 can be used in research related to osteolytic bone diseases and myocardial infarction.

SC-19220 is a prostaglandin E₂ receptor EP1 antagonist. SC-19220 blocks functional EP1 receptor activation, and RANK/RANKL signaling pathway. SC-19220 inhibits osteoclast formation and bone resorption by pre-existing osteoclasts. SC-19220 can be used for the research of osteoporotic disorders, inflammatory bone resorption.

Y2641, a etrahydro-β-carboline derivative, is an orally active dual RANKL/TNF-α inhibitor with K_d values of 3.984 μM and 18.59 μM for RANKL and TNF-α, respectively. Y2641 inhibits RANKL-induced osteoclastogenic and has anti-inflammatory and cartilage destruction. Y2641 can be used for study of osteoarthritis.

SPA0355 is a thiourea derivative that has antioxidant and anti-inflammatory properties. SPA0355 inhibits the RANKL (receptor activator of nuclear factor κB ligand) induced osteoclast formation in primary bone marrow-derived macrophages. SPA0355 also suppresses the activation of the MAPKs, Akt, and NF-κB pathways. Additionally, SPA0355 promotes osteoblast differentiation, increases alkaline phosphatase activity, and enhances mineral nodule formation. SPA0355 can protect ovariectomized mice from bone loss by stimulating osteoblast differentiation and inhibiting osteoclast resorption, making it useful for studying postmenopausal osteoporosis.

RANKL-IN-1 is a selective and orally active Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) inhibitor with a K_D value of 7.6 μM. RANKL-IN-1 exhibits inhibitory activity and selectivity against osteoclastogenesis with an IC₅₀ value of 0.07 μM and SI of 82.57. RANKL-IN-1binds directly to RANKL and blocks the RANKL-induced activation of the NF-κB and MAPK pathways. RANKL-IN-1 can be used for the research of metabolic disease, such as osteoporosis.

Physalin D is isolated from the aerial parts of Physalis angulate. Physalin D displays considerable cytotoxicity against several cancer cell lines, showing IC₅₀ values in the range of d 0.28 to 2.43 microg/mL. Physalin D has the potential for the cancer disease.