Musculoskeletal and Skin Disease

Chloroquine is an antimalarial and anti-inflammatory agent widely used to treat malaria and rheumatoid arthritis. Chloroquine is an autophagy and toll-like receptors (TLRs) inhibitor. Chloroquine is highly effective in the control of SARS-CoV-2 (COVID-19) infection in vitro (EC₅₀=1.13 μM).

LY294002 is a broad-spectrum inhibitor of PI3K with IC₅₀s of 0.5, 0.57, and 0.97 μM for PI3Kα, PI3Kδ and PI3Kβ, respectively. LY294002 also inhibits CK2 with an IC₅₀ of 98 nM. LY294002 is a competitive DNA-PK inhibitor that binds reversibly to the kinase domain of DNA-PK with an IC₅₀ of 1.4 μM. LY294002 is an apoptosis activator.

Trametinib (GSK1120212; JTP-74057) is an orally active MEK inhibitor that inhibits MEK1 and MEK2 with IC₅₀s of about 2 nM. Trametinib activates autophagy and induces apoptosis, cross the blood-brain barrier (BBB), used in research related to subarachnoid hemorrhage (SAH).

Ruxolitinib (INCB18424) is an orally active and selective JAK1/2 inhibitor with IC₅₀s of 3.3 nM and 2.8 nM in cell-free assays, and has 130-fold selectivity for JAK1/2 over JAK3. Ruxolitinib induces autophagy and kills tumor cells through toxic mitophagy.

DAPT (GSI-IX) is a potent and orally active γ-secretase inhibitor with IC₅₀s of 115 nM and 200 nM for total amyloid-β (Aβ) and Aβ₄₂, respectively. DAPT inhibits the activation of Notch 1 signaling and induces cell differentiation. DAPT also induces autophagy and apoptosis. DAPT has neuroprotection activity and has the potential for autoimmune and lymphoproliferative diseases, degenerative disease and cancers treatment.

N-Ethylmaleimide (NEM) derives from maleic acid, it can alkylates free sulfhydryl. N-Ethylmaleimide is an irreversible cysteine protease inhibitor. N-ethylmaleimide specific inhibits phosphate transport in mitochondria. N-Ethylmaleimide inhibits prolyl endopeptidase with an IC₅₀ value of 6.3 μM. N-Ethylmaleimide can be used to modify cysteine residues in proteins and peptides.

Tofacitinib (Tasocitinib) is an orally active, blood-brain barrier permeable selective inhibitor of JAK1/JAK3. Tofacitinib blocks the JAK-STAT/NF-κB signaling pathway, inhibits cytokine signal transduction, phosphorylation of STAT1/STAT5, and suppresses innate and adaptive immune responses. Tofacitinib can be used in research related to major depressive disorder, rheumatoid arthritis, pulmonary diseases, systemic lupus erythematosus, and immune-mediated liver injury.

CX-5461 is a selective, orally active RNA polymerase I inhibitor. CX-5461 disrupts the formation of the SL1-rDNA complex, thereby blocking the transcription initiation of ribosomal RNA without altering the activity of RNA polymerase II, DNA replication, or protein translation processes. CX-5461 upregulates the expression of p21, MDM2, Sestrin1/2, and phosphorylated AMPKα, and reduces the level of phosphorylated Akt. CX-5461 induces G2/G2/M cell cycle arrest, Autophagy, Apoptosis, and cellular senescence, and activates CHK1, CHK2, and RPA. CX-5461 can be used in research related to osteosarcoma, cervical cancer, hematologic malignancies, high-grade serous ovarian cancer, and solid tumors.

CCCP is an oxidative phosphorylation (OXPHOS) uncoupler. CCCP induces activation of PINK1 leading to Parkin Ser65 phosphorylation.

Quercetin, a natural flavonoid, is a stimulator of recombinant SIRT1 and also a PI3K inhibitor with IC₅₀ of 2.4 μM, 3.0 μM and 5.4 μM for PI3K γ, PI3K δ and PI3K β, respectively.

Adezmapimod (SB 203580) is a selective and ATP-competitive p38 MAPK inhibitor with IC₅₀s of 50 nM and 500 nM for SAPK2a/p38 and SAPK2b/p38β2, respectively. Adezmapimod inhibits LCK, GSK3β and PKBα with IC₅₀s of 100-500-fold higher than that for SAPK2a/p38. Adezmapimod can inhibit p38 MAPK and lead to the inhibition of downstream HSP27 phosphorylation. Adezmapimod does not disrupt JNK activity and is an autophagy and mitophagy activator.

Decitabine (NSC 127716) is an orally active deoxycytidine analogue antimetabolite and DNA methyltransferase inhibitor. Decitabine incorporates into DNA in place of cytosine can covalently trap DNA methyltransferase to DNA causing irreversible inhibition of the enzyme. Decitabine induces cell G2/M arrest and cell Apoptosis. Decitabine has potent anticancer activity.

Polyinosinic-polycytidylic acid (Poly(I:C)) is a synthetic analog of double-stranded RNA and an agonist of toll-like receptor 3 (TLR3) and retinoic acid inducible gene I (RIG-I)-like receptors (RIG-I and MDA5). Polyinosinic-polycytidylic acid can be used as a vaccine adjuvant to enhance innate and adaptive immune responses, and to alter the tumor microenvironment. Polyinosinic-polycytidylic acid can directly trigger cancer cells to undergo apoptosis.

5-Azacytidine (Azacitidine; 5-AzaC; Ladakamycin) is a nucleoside analogue of cytidine that specifically inhibits DNA methylation. 5-Azacytidine is incorporated into DNA to covalently trap DNA methyltransferases and contributes to reverse epigenetic changes. 5-Azacytidine induces cell autophagy.

Resatorvid (TAK-242) is a selective Toll-like receptor 4 (TLR4) inhibitor. Resatorvid inhibits NO, TNF-α and IL-6 production with IC_50s of 1.8 nM, 1.9 nM and 1.3 nM, respectively. Resatorvid downregulates expression of TLR4 downstream signaling molecules MyD88 and TRIF. Resatorvid inhibits autophagy and plays pivotal role in various inflammatory diseases.

Nigericin is an antibiotic derived from Streptomyces hygroscopicus that act as a K⁺/H⁺ ionophore, promoting K⁺/H⁺ exchange across mitochondrial membranes. Nigericin is a NLRP3 activator. Nigericin shows promising anti-cancer activities through decreasing intracellular pH (pHi), and inactivation of Wnt/β-catenin signals. Nigericin induces pyroptosis through caspase 1/GSDMD in TNBC.

SB 202190 is a selective p38 MAP kinase inhibitor with IC₅₀s of 50 nM and 100 nM for p38α and p38β2, respectively. SB 202190 binds to the ATP pocket of the active recombinant human p38 kinase with a K_d of 38 nM. SB 202190 has anti-cancer activity and rescued memory deficits. SB202190 induces autophagy.

Mirdametinib (PD0325901) is an orally active, selective and non-ATP-competitive MEK inhibitor with an IC₅₀ of 0.33 nM. Mirdametinib exhibits a K_i^app of 1 nM against activated MEK1 and MEK2. Mirdametinib suppresses the expression of p-ERK1/2 and induces apoptosis. Mirdametinib has anti-cancer activity for a broad spectrum of human tumor xenografts.

Corticosterone (17-Deoxycortisol) is an orally active and adrenal cortex-produced glucocorticoid, which plays an important role in regulating neuronal functions of the limbic system (including hippocampus, prefrontal cortex, and amygdala). Corticosterone increases the Rab-mediated AMPAR membrane traffic via SGK-induced phosphorylation of GDI. Corticosterone also interferes with the maturation of dendritic cells and shows a good immunosuppressive effect.

Methotrexate (Amethopterin; CL14377; WR19039) is an orally active antifolate (Antifolate). Methotrexate inhibits dihydrofolate reductase (DHFR), blocks tetrahydrofolate production, suppresses purine/pyrimidine synthesis and transmethylation, and causes intracellular accumulation of AICAR. Methotrexate promotes extracellular adenosine release, regulates the cytokine network, and inhibits the alarmin function of HMGB1. Methotrexate induces apoptosis and cytotoxicity, upregulates the expression of iNOS and COX-2, suppresses hippocampal neurogenesis, and induces pulmonary fibrosis. Methotrexate is used in the research of various immune and inflammation-related diseases such as arthritis, psoriasis, systemic lupus erythematosus, as well as pulmonary fibrosis and breast cancer.