Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus?
Abstract
:1. Muscle Cachexia
2. STAT3 Protein
3. STAT3 Protein in Oncogenesis
4. STAT3 Protein in Skeletal Muscle
5. STAT3 Protein in Cancer Cachexia
6. Synthetic STAT3 Inhibitors in Anticancer Therapy
7. Natural STAT3 Inhibitors
8. Perspectives
Funding
Conflicts of Interest
References
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Compound | Mechanism of Action | Indication | Clinical Trial ID | Chemical Structure |
---|---|---|---|---|
Anamorelin hydrochloride | selective agonist of the ghrelin/growth hormone secretagogue receptor | cancer cachexia, non–small-cell lung cancer (NSCLC) | NCT03743064, NCT03637816, NCT03743051, NCT01387269, NCT01387282, NCT03035409, NCT01395914, NCT00622193 | PubChem Identifier: CID 9828911, https://pubchem.ncbi.nlm.nih.gov/compound/Anamorelin |
Relamorelin (RM-131) | selective agonist of the ghrelin/growth hormone secretagogue receptor | anorexia nervosa | NCT01642550 | PubChem Identifier: CID 85364156, https://pubchem.ncbi.nlm.nih.gov/compound/Relamorelin |
NGM120 Monoclonal antibody against GDNP protein alpha-like receptor (GFRAL)–3P10 antibody | GDNF family receptor-α-like (GFRAL)-Ret proto-oncogene (RET) blocker | cancer cachexia | NCT04068896 | |
Vitamin D | promotion of lipid partitioning and muscle metabolic function | cancer cachexia | NCT03144128 | PubChem Identifier: CID 5280795, https://pubchem.ncbi.nlm.nih.gov/compound/Cholecalciferol |
Branched Chain Amino Acid (BCAA) | regulation of the anabolic pathway of muscle synthesis | sarcopenia in chronic liver disease | NCT04246918 | |
Omega-3 fatty acids | regulation of cell signaling, cell structure, and fluidity of membranes | cancer cachexia | NCT01596933, NCT00031707 | |
Beta-hydroxy-beta-methyl butyrate (HMB) | improvement of muscle hypertrophy and strength, aerobic performance, resistance to fatigue, and regenerative capacity | critical illness, cancer cachexia | NCT03464708, NCT03151291 | PubChem Identifier: CID 9860341, https://pubchem.ncbi.nlm.nih.gov/compound/Calcium-beta-hydroxy-beta-methylbutyrate |
Compound | Mechanism of Action | Indication | Clinical trial ID | Chemical Structure |
---|---|---|---|---|
WP1066 | cell-permeable JAK2, STAT3, STAT5, and ERK1/2 inhibitor, responsible for the dephosphorylation and nuclear export of constitutively phosphorylated STAT3 | metastatic malignant neoplasms in the brain; metastatic melanoma; recurrent glioblastoma; recurrent brain neoplasm | NCT04334863 NCT01904123 | PubChem Identifier: CID 11210478, https://pubchem.ncbi.nlm.nih.gov/compound/wp1066 |
OPB-31121 | potent inhibition of STAT3 and STAT5 phosphorylation without upstream kinase inhibition | advanced cancer, solid tumors, hepatocellular carcinoma | NCT00955812 NCT01406574 | |
TTI-101 | binaphthol sulfonamide-based inhibitor of STAT3 that specifically targets and binds to the phosphotyrosine peptide-binding site within the Src homology 2 (SH2) domain of STAT3 | breast cancer, head, and neck squamous cell carcinoma, non–small-cell lung cancer, colorectal cancer, gastric adenocarcinoma, melanoma | NCT04068896 | PubChem Identifier: SID 382371065, 432001-19-9, https://pubchem.ncbi.nlm.nih.gov/substance/382371065 |
Pyrimethamine | synthetic derivative of ethyl-pyrimidine, a competitive inhibitor of dihydrofolate reductase (DHFR)—a key enzyme in the redox cycle for tetrahydrofolate production; a cofactor required for DNA and proteins synthesis | relapsed chronic lymphocytic leukemia, small lymphocytic lymphoma | NCT01066663 | PubChem Identifier: CID 4993, https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimethamine |
OPB-51602 | inhibition of STAT3 phosphorylation and activation of STAT3 | advanced solid tumors: breast cancer, head, and neck squamous cell carcinoma, non–small-cell lung cancer, hepatocellular cancer, colorectal cancer, gastric adenocarcinoma, melanoma | NCT01423903 NCT01344876 NCT01184807 | |
Napabucasin (Napa, BBI608) | STAT3 and cancer cell stemness inhibitor | gastrointestinal malignancies, pancreatic cancer, GBM | NCT03721744 NCT02753127 NCT03522649 | PubChem Identifier: CID 10331844 https://pubchem.ncbi.nlm.nih.gov/compound/Napabucasin |
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Jaśkiewicz, A.; Domoradzki, T.; Pająk, B. Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus? Int. J. Mol. Sci. 2020, 21, 8261. https://doi.org/10.3390/ijms21218261
Jaśkiewicz A, Domoradzki T, Pająk B. Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus? International Journal of Molecular Sciences. 2020; 21(21):8261. https://doi.org/10.3390/ijms21218261
Chicago/Turabian StyleJaśkiewicz, Anna, Tomasz Domoradzki, and Beata Pająk. 2020. "Targeting the JAK2/STAT3 Pathway—Can We Compare It to the Two Faces of the God Janus?" International Journal of Molecular Sciences 21, no. 21: 8261. https://doi.org/10.3390/ijms21218261