Introduction of JAK-STAT signaling Pathway
The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines, which is involved in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Compared with other signal pathways, this signal pathway is relatively simple, it mainly consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT. JAK kinase mediates signal transduction of most cytokines in cells. Such as interleukin (IL), interferon (IFN), erythropoietin (EPO), granulocyte and macrophage colony-stimulating factor (GM-CSF), growth-promoting factor (GH), prolactin (PRL), thrombopoietin (TPO), Platelet-derived factor (PDGF) and epidermis Cell growth factor (EGF), etc. Moreover, different receptors can activate different subtypes of JAK kinases, thus showing different biological functions.
JAK kinase drug target
JAK kinase is a very important drug target, and JAK inhibitors developed for this target are mainly used to screen drugs for the treatment of hematological diseases, tumors, rheumatoid arthritis, and psoriasis. JAK-1, JAK-2, and TYK-2 were expressed in all tissues and cells of the human body. JAK-3 was mainly expressed in hematopoietic tissue cells, mainly in bone marrow cells, thymocytes, NK cells, activated B lymphocytes and T lymphocytes.
JAK1 binds to IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, and IFN- α, IFN- γ, IL-6 in the gp130 family and other receptors containing γ c. JAK1 has become a new target in the field of immunity, inflammation, and cancer.
JAK2 plays an important role in the regulation of many receptors, including EPO, GH, PRL, IFN- γ and IL-3, IL-5, GM-CSF, a member of the β c family. A base mutation JAK2V617F, which is closely related to the occurrence of polycythemia vera (PV) idiopathic thrombocytosis (ET) idiopathic myelofibrosis (IMF) and chronic myelogenous leukemia (CML) in myeloproliferative diseases. Therefore, JAK2 has become the exact target for the treatment and prevention of this kind of disease.
JAK3 regulates cell signal transduction by binding to γ cochain (γ c) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Both JAK3 and γ c mutations can lead to severe combined immunodeficiency. The abnormal activity of JAK3 is characterized by the decrease of T and NK cells and the loss of function of B cells, which seriously affects the normal biological functions of the immune system. Because of its functional characteristics and special tissue distribution, JAK3 has become an attractive drug target for immune system-related diseases.
TYK2 is the first member of JAK family, which can be activated by IFNs, IL-10, IL-6, IL-12, IL-23, IL-27 and other receptors. In mice, TYK2 dysfunction can lead to a variety of cytokine receptor signaling pathway defects, resulting in viral infection, decreased antibacterial immune function and increased the possibility of pulmonary infection.
| Phase | Chemical Name/Description | Code Name (CD) | Generic Name (GN) | Organization | Condition |
| Preclinical | 2-(2-Benzothiazolyl)-2-[2-[4-(morpholin-4-ylmethyl)benzyloxy]pyrimidin-4-yl]acetonitrile | SP-600125 | SP-600125 | Celgene (Originator); | Arthritis; Malaria; Asthma; Cancer, breast |
| Preclinical | D-Threonyl-D-aspartyl-D-glutaminyl-D-seryl-D-arginyl-D-prolyl-D-valyl-D-glutaminyl-D-prolyl-D-phenylalanyl-D-leucyl-D-asparaginyl-D-leucyl-D-threonyl-D-threonyl-D-prolyl-D-arginyl-D-lysyl-D-prolyl-D-arginyl-D-prolyl-D-prolyl-D-arginyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D-arginyl-D-lysyl-D-lysyl-D-arginyl-glycinamide | AS-600292 | AS-600292 | Applied Research Systems (Originator); | Stroke |
| Preclinical | 6-Bromo-2-[4-(methylsulfonyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester | AGI-1095 | AGI-1095 | AtheroGenics (Originator); | Hyperlipidemia |
| Preclinical | N-(7-Methoxy-11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)-2-methylbenzamide | SPC-0009766; SPC-9766 | SPC-0009766; SPC-9766 | Celgene (Originator); | Epilepsy; Stroke |
| Preclinical | 3-(4-Fluorophenyl)-5-(1H-1,2,4-triazol-3-yl)-1H-indazole | Rhamnetin | Warszawski Uniwersytet Medyczny; | Inflammation; Coronary artery disease; Cancer | |
| Preclinical | 3-(6-Chloro-1-oxo-4-phenyl-3-propionyl-1,2-dihydroisoquinolin-2-ylmethyl)-N-cyclopropyl-1-methyl-1H-pyrazole-5-carboxamide | AS-601245 | AS-601245 | Merck Serono (Originator); | Arthritis; Stroke, ischemic; Myocardial infarction |
| Preclinical | N-[4-(4-Phenoxy-1H-pyrazolo[4,3-c]pyridin-3-ylaminomethyl)phenyl]acetamide | D-JNKI-1; D-JNKi; D-TAT-JBD20; D-TAT-JNKI | D-JNKI-1; D-JNKi; D-TAT-JBD20; D-TAT-JNKI | Xigen (Originator); Centre Hospitalier Universitaire Vaudois (Originator); | Stroke, ischemic |
| Preclinical | 4-[2-(4-Fluorophenyl)-5(S)-(4-methoxybenzyloxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]-N-propylpyrimidin-2-amine | Celgene (Originator); | Arthritis; Asthma; Diabetes | ||
| Preclinical | N-[2′-(Phenylamino)-4,4′-bipyridin-2-yl]tetrahydrofuran-3-carboxamide | Takeda (Originator); | Heart failure; Coronary artery disease | ||
| Preclinical | 3-(1H-Imidazol-4-yl)-2(Z)-propenoic acid | AstraZeneca (Originator); | Dementia, Alzheimer’s type | ||
| Preclinical | N-(4-Amino-5-cyano-6-ethoxypyridin-2-yl)-2-[2,5-dimethoxy-4-(methylsulfonyl)phenyl]acetamide | CC-0209766 | CC-0209766 | Celgene (Originator); | Immunological Disorders |
| Preclinical | N-(4-Amino-5-chloro-6-ethoxypyridin-2-yl)-2-[2,5-dimethoxy-4-(methylsulfonyl)phenyl]acetamide | CC-0223105 | CC-0223105 | Celgene (Originator); | Immunological Disorders |
| Preclinical | 4-Amino-5-chloro-6-ethoxy-N-[4-(methylsulfonyl)benzyl]pyridine-2-carboxamide | Eisai (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | N-[3-(2-Naphthyl)-1H-indazol-5-yl]cyclopropanecarboxamide | AstraZeneca (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | 4-Amino-5-cyano-6-(cyclopropylmethoxy)-N-[4-(methylsulfonyl)benzyl]pyridine-2-carboxamide | Abbott (Originator); | Arthritis; Diabetes | ||
| Preclinical | 4-Amino-5-cyano-N-[4-(methylsulfonyl)benzyl]-6-(3-thienyl)pyridine-2-carboxamide | Abbott (Originator); | Arthritis; Diabetes | ||
| Preclinical | N-[2-[N-[5-tert-Butyl-2-methoxy-3-(methylsulfonamido)phenyl]carbamoyl]-1-benzothien-7-yl]-6-(cyclopropylamino)pyridine-3-carboxamide | Abbott (Originator); | Arthritis; Diabetes | ||
| Preclinical | ER-181304 | ER-181304 | Eisai (Originator); | Parkinson’s disease | |
| Preclinical | 3-(1-Methyl-1H-pyrazol-4-yl)-5-[trans-4-(4-morpholinyl)cyclohexyl]-1H-pyrrolo[2,3-b]pyridine | Abbott (Originator); | Diabetes | ||
| Preclinical | 3-(1-Methyl-1H-pyrazol-4-yl)-5-[trans-4-(perhydro-1,4-oxazepin-4-yl)cyclohexyl]-1H-pyrrolo[2,3-b]pyridine | Abbott (Originator); | Diabetes | ||
| Preclinical | 4-(2,3-Dihydro-1,4-benzodioxin-6-yl)-5-(5-nitrothiazol-2-ylsulfanyl)-4H-1,2,4-triazol-3-ol | Boehringer Ingelheim (Originator); | Inflammatory bowel disease; Psoriasis; Rheumatoid arthritis | ||
| Preclinical | 7-Chloro-3-[4-[N-(2-hydroxyethyl)carbamoyl]benzyl]-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester | AS-01 | AS-01 | Merck Serono (Originator); | Endometriosis |
| Preclinical | Combination of betamethasone dipropionate and bexarotene | ER-409903 | ER-409903 | Eisai (Originator); | Multiple sclerosis |
| Preclinical | 5-(5-Nitrothiazol-2-ylsulfanyl)-1,3,4-thiadiazol-2-amine | ER-417258 | ER-417258 | Eisai (Originator); | Multiple sclerosis |
| Preclinical | trans-4-[4-[3-(Tetrahydropyran-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-ylamino]cyclohexanol | BI-78D3 | BI-78D3 | Sanford Burnham Prebys Med Discov Inst; | Diabetes type 2 |
| Preclinical | N-[4-(3-Methyl-1H-1,2,4-triazol-1-yl)phenyl]-4-[3-(4-morpholinyl)phenyl]pyrimidin-2-amine | Roche (Originator); | Asthma; Rheumatoid arthritis | ||
| Preclinical | 3-[2-[4-(2-Methyl-2H-tetrazol-5-yl)phenylamino]pyrimidin-4-yl]-5-(4-morpholinyl)benzonitrile | SU-3327 | SU-3327 | Life Technologies; Tocris; Sanford Burnham Prebys Med Discov Inst; | Traumatic brain injury; Diabetes type 2; Coronary artery disease |
| Preclinical | 3-(4-Morpholinyl)-5-[2-[4-[3-(2-pyridyl)-1H-1,2,4-triazol-1-yl]phenylamino]pyrimidin-4-yl]benzonitrile | Pfizer (Originator); | Diabetes type 2; Obesity | ||
| Preclinical | 4-[3-Fluoro-5-(4-morpholinyl)phenyl]-N-[4-[3-(4-morpholinyl)-1H-1,2,4-triazol-1-yl]phenyl]pyrimidin-2-amine | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | N-[4-Chloro-3-(1H-1,2,4-triazol-3-yl)-2-thienyl]-2-(5-isoquinolinyl)acetamide | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | 8-Chloro-7-(1-methyl-1H-pyrazol-4-yl)-N-[4-[3-(4-morpholinyl)-1H-1,2,4-triazol-1-yl]phenyl]quinazolin-2-amine | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | 7-(1-Methyl-1H-pyrazol-4-yl)-N-[4-[3-(4-morpholinyl)-1H-1,2,4-triazol-1-yl]phenyl]quinazolin-2-amine | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | trans-4-[4-[4-[4-(Methylsulfonyl)piperidin-1-yl]-1H-indol-1-yl]pyrimidin-2-ylamino]cyclohexanol | ELN-864404 | ELN-864404 | Perrigo (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type |
| Preclinical | 5-Chloro-4-(1-methyl-1H-pyrazol-3-yl)-N-[4-[3-(4-morpholinyl)-1H-1,2,4-triazol-1-yl]phenyl]pyridin-2-amine | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Cognitive disorders; Parkinson’s disease | ||
| Preclinical | 5-Fluoro-4-(1-methyl-1H-pyrazol-3-yl)-N-[4-[3-(6-methylpyridin-3-yl)-1H-1,2,4-triazol-1-yl]phenyl]pyridin-2-amine | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Cognitive disorders; Parkinson’s disease | ||
| Preclinical | 5-Fluoro-4-(1-methyl-1H-pyrazol-3-yl)-N-[4-[3-(2-pyridyl)-1H-1,2,4-triazol-1-yl]phenyl]pyridin-2-amine | Roche (Originator); | Dementia, Alzheimer’s type; Asthma; Diabetes; Rheumatoid arthritis; Parkinson’s disease | ||
| Preclinical | 4-[5-(1-Cyclopropyl-2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine | Scripps Research Institute (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | N-[4-[3-(6-Methylpyridin-3-yl)-1H-1,2,4-triazol-1-yl]phenyl]-4-[3-(4-morpholinyl)phenyl]pyrimidin-2-amine | Scripps Research Institute (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | N-[4-[4-(1H-Indazol-3-yl)benzamido]butyryl]glycylglycyl-D-leucyl-D-asparaginyl-D-leucyl-D-threonyl-D-threonyl-D-prolyl-D-arginylglycylglycyl-D-arginyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D-arginyl-D-lysyl-D-lysyl-D-arginyl-glycinamide; N-[4-[4-(1H-Indazol-3-yl)benzamido]butyryl]GGlnlttprGGrrrqrrkkrG-NH2 | Scripps Research Institute (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | N-[4-Bromo-3-(1H-1,2,4-triazol-5-yl)thien-2-yl]-2-(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl)acetamide | CHDI-00372893 | CHDI-00372893 | CHDI Foundation; Albany Molecular Research; BioFocus; | Huntington’s disease |
| Preclinical | N-[4-Bromo-3-(1H-1,2,4-triazol-5-yl)thien-2-yl]-2-(6,7-difluoro-2-oxo-1,2-dihydroquinolin-1-yl)acetamide | SR-3306 | SR-3306 | Scripps Research Institute (Originator); OPKO; | Heart failure; Parkinson’s disease |
| Preclinical | N-[4-Bromo-3-(1H-1,2,4-triazol-5-yl)thien-2-yl]-2-[2-oxo-6-(trifluoromethyl)1,2-dihydroquinolin-1-yl]acetamide | Sanford Burnham Prebys Med Discov Inst (Originator); | Diabetes | ||
| Preclinical | 2-[2-(4-Methoxyphenoxy)-5-(trifluoromethyl)pyridin-4-ylamino]benzamide | IGP-002 | IGP-002 | Perrigo (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type |
| Preclinical | 2-[5-Chloro-2-(4-methoxyphenoxy)pyridin-4-ylamino]benzamide | Perrigo (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type | ||
| Preclinical | N2-(trans-4-Aminocyclohexyl)-9-cyclopentyl-N8-(2,4-difluorophenyl)-9H-purine-2,8-diamine | IGP-001 | IGP-001 | Perrigo (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type |
| Preclinical | (2E,6E)-2,6-Bis[2-(trifluoromethyl)benzylidene]cyclohexanone | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type; Parkinson’s disease; Cancer | ||
| Preclinical | Sodium [(11Z)-11H-indeno[1,2-b]quinoxalin-11-ylideneamino]oxidanide | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type; Parkinson’s disease; Cancer | ||
| Preclinical | Methyl 3-[4-[[(1R*,2S*,3S*,7S*)-5-hydroxytricyclo[3.3.1.1(3,7)]dec-2-yl]carbamoyl]benzyl]-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridine-2-carboxylate | CC-359; JNK-359 | CC-359; JNK-359 | Celgene (Originator); Ligand (Originator); | Ischemia-reperfusion injury |
| Preclinical | Methyl 3-[4-[(trans-4-hydroxycyclohexyl)carbamoyl]benzyl]-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridine-2-carboxylate | C-66 | C-66 | Mudanjiang Medical University (MMU) (Originator); Wenzhou Medical University (Originator); Nanjing University of Science Technology (Originator); | Cardiopathy, diabetic; Nephropathy, diabetic; Inflammation; Cancer |
| Preclinical | (4-Hydroxypiperidin-1-yl)[trans-4-[[4-[4-[3-(methylsulfonyl)propoxy]-1H-indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone | IQ-1S | IQ-1S | Altai State Technical University; Montana State University; | Neurodegeneration; Stroke, ischemic; Inflammation; Immunosuppression |
| Preclinical | 3-[5-[(2-Chloro-3-methylphenyl)amino]-1H-indazol-1-yl]-N-[2-(4-cyclobutylpiperazin-1-yl)ethyl]benzamide | Roche (Originator); | Renal Disorders | ||
| Preclinical | 3-[5-[(2-Chlorophenyl)amino]-1H-indazol-1-yl]-N-[3-(morpholin-4-yl)propyl]benzamide | Roche (Originator); | Renal Disorders | ||
| Preclinical | 3-[[4-(Dimethylamino)but-2-enoyl]amino]-N-[3-methyl-4-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]phenyl]benzamide | Roche (Originator); | Rheumatoid arthritis | ||
| Preclinical | 3-[5-[(2-Fluorophenyl)amino]-1H-indazol-1-yl]-N-(3,4,5-trimethoxyphenyl)benzamide | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | 4-[5-[(2-Chlorophenyl)amino]-1H-indazol-1-yl]-N-[3-(morpholin-4-yl)propyl]benzamide | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | dqsrpvqpflnlttprkprpprrrqrrkkrG-NH2; D-alpha-Aspartyl-D-glutaminyl-D-seryl-D-arginyl-D-prolyl-D-valyl-D-glutaminyl-D-prolyl-D-phenylalanyl-D-leucyl-D-asparaginyl-D-leucyl-D-threonyl-D-threonyl-D-prolyl-D-arginyl-D-lysyl-D-prolyl-D-arginyl-D-prolyl-D-prolyl-D-arginyl-D-arginyl-D-arginyl-D-glutaminyl-D-arginyl-D-arginyl-D-lysyl-D-lysyl-D-arginylglycinamide | JNK-IN-8 | JNK-IN-8 | Dana-Farber Cancer Institute (Originator); | Cancer, breast |
| Preclinical | 3-[5-(Cyclohexylamino)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]benzenesulfonamide | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | N-[3-[5-(Cyclohexylamino)-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]phenyl]acetamide | Scripps Research Institute (Originator); | Parkinson’s disease | ||
| Preclinical | 4-[4-(1-Methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]-N-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]pyridin-2-amine | OncoTherapy Science (Originator); Shionogi; | Cancer | ||
| Preclinical | 4-[4-(5-Methyl-1H-pyrazol-4-yl)-1,2-oxazol-3-yl]-N-[4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]pyridin-2-amine | OncoTherapy Science (Originator); Shionogi; | Cancer | ||
| Preclinical | 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl](carboxy-11C)benzoic acid | Scripps Research Institute (Originator); | Stroke; Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | D-Arginyl-L-lysyl-L-lysyl-L-arginyl-D-arginyl-L-glutaminyl-L-arginyl-L-arginyl-D-arginyl-L-arginyl-L-prolyl-D-lysyl-L-arginyl-L-prolyl-D-alanyl-L-threonyl-L-leucyl-L-asparaginyl-L-leucyl-D-phenylalaninamide; rKKRrQRRrRPkRPaTLNLf-NH2 | [11C]Bexarotene | General Hospital Corp. (Originator); | Diagnostics | |
| Preclinical | 3-(4-[[(2-Chlorophenyl)carbamoyl]amino]-1H-pyrazol-1-yl)-N-[(6-methylpyridin-3-yl)methyl]benzamide | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | 3-(4-[[(2-Chlorophenyl)carbamoyl]amino]-1H-pyrazol-1-yl)-N-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]benzamide | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | 3-(4-[[(2-Chlorophenyl)carbamoyl]amino]-1H-pyrazol-1-yl)-N-[1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl]benzamide | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | 3-(4-[[(2-Chlorophenyl)carbamoyl]amino]-1H-pyrazol-1-yl)-N-(piperidin-4-ylmethyl)benzamide | Scripps Research Institute (Originator); | Dementia, Alzheimer’s type; Parkinson’s disease | ||
| Preclinical | N-(2-Furylmethyl)-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-[5-(4-Methoxyphenyl)-1,2-oxazol-3-yl]-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | 5-Phenyl-N-(2-sulfanyl-1H-benzimidazol-5-yl)-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-Cyclopropyl-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | 5-Phenyl-N-(pyridin-2-yl)-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-(4-Nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-(4-Chloro-3-fluorophenyl)-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-(4-Fluorobenzyl)-5-phenyl-1H-pyrazole-3-carboxamide | Indian Institute of Chemical Technology (Originator); Kakatiya University (Originator); | Inflammation | ||
| Preclinical | N-[trans-4-[(8-Isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]-2-methylpropanamide | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type | ||
| Preclinical | 1-Ethyl-3-[trans-4-[(8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]urea | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type | ||
| Preclinical | 1-Isopropyl-3-[trans-4-[(8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]cyclohexyl]urea | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type | ||
| Preclinical | N-Ethyl-4-[(8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]piperidine-1-carboxamide | Scripps Research Institute (Originator); | Stroke; Arthritis; Dementia, Alzheimer’s type | ||
| Preclinical | N-(4,4-Difluorocyclohexyl)-4-[3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-4-yl]pyrimidin-2-amine | Evotec (Originator); | Huntington’s disease | ||
| Preclinical | trans-4-([4-[1-Isopropyl-5-(1-methylcyclopropyl)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexanol | Evotec (Originator); | Huntington’s disease | ||
| Preclinical | trans-4-[[4-(5-Isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl]amino]cyclohexanecarbonitrile | Evotec (Originator); | Huntington’s disease | ||
| Preclinical | trans-4-([4-[3-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl]amino)cyclohexanol | Evotec (Originator); | Huntington’s disease | ||
| Preclinical | 2-(tert-Butylamino)-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]pyrimidine-5-carboxamide | Signal Pharm. (d/b/a Celgene Research) (Originator); | Hepatitis, viral; Idiopathic pulmonary fibrosis; Hepatic steatosis; Cirrhosis | ||
| Preclinical | 2-([5-Chloro-2-[(1,3-thiazol-2-ylmethyl)amino]pyrimidin-4-yl]amino)-6-fluorobenzamide | GSK-2226649A; GSK-649A | GSK-2226649A; GSK-649A | GlaxoSmithKline (Originator); | Musculoskeletal and Connective Tissue Disorders |
| Preclinical | N4-Cyclohexyl-N2-[2-methoxy-4-(morpholin-4-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine | Ohio State University (Originator); | Cancer, breast | ||
| Preclinical | Small interfering RNA (siRNA) targeting c-Jun N-terminal kinase-2 (JNK-2) incorporated into a nanoparticles comprising 21-mer nontoxic amphipatic cationic peptide | JNK2 siRNA NP; anti-JNK2 siRNA NP | JNK2 siRNA NP; anti-JNK2 siRNA NP | Washington University (Originator); | Atherosclerosis |
| Preclinical | N-[4-[4-(4-Fluorophenyl)-1-methyl-2-(methylsulfanyl)-1H-imidazol-5-yl]pyridin-2-yl]acetamide | CBS-3408 | CBS-3408 | c-a-i-r biosciences (Originator); | Rheumatoid arthritis |
| Preclinical | 4-[4-(4-Fluorophenyl)-2-(methylsulfanyl)-1H-imidazol-5-yl]-N-phenylpyridin-2-amine | CBS-3435 | CBS-3435 | c-a-i-r biosciences; Merckle GmbH (Originator); | Rheumatoid arthritis |
| Preclinical | 4-Chloro-N-[3-([4-[3-(3-hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl]pyridin-2-yl]amino)propyl]benzene-1-sulfonamide | Korea Institute of Science & Technology (Originator); National Research Centre of Egypt (NRC) (Originator); Mansoura University (Originator); University of Science Technology Korea (Originator); University of Sharjah (Originator); | Cancer | ||
| Phase I | L-Arginyl-D-tryptophyl-(N-methyl)-L-phenylalanyl-D-tryptophyl-L-leucyl-L-methioninamide; [Arg6,D-Trp7,9,MePhe8]-Substance P(6-11) | PTL-68001; PTL-68300B | PTL-68001; PTL-68300B, Antagonist-G | Teva; Cancer Research UK (Originator); | Cancer |
| Phase I | Succinic acid 2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenyl monoester | CC-401; JNK-401 | CC-401; JNK-401 | Celgene (Originator); Signal Pharm. (d/b/a Celgene Research) (Originator); | Leukemia, acute myeloid; Glomerulonephritis; Obesity; Inflammation; Diabetes |
| Phase II | Anthra[1,9-cd]pyrazol-6(2H)-one | AS-602801; PGL-5; PGL-5001 | AS-602801; PGL-5; PGL-5001, Bentamapimod (Prop INN) | PregLem; Merck Serono (Originator); | Multiple sclerosis; Endometriosis; Fibrosis, cystic |
| Phase II | N-[5-[4-(1H-1,2,3-Benzotriazol-1-yl)piperidin-1-ylsulfonyl]thien-2-ylmethyl]-4-chlorobenzamide | Cis-UCA | Cis-UCA, Cis-urocanic acid, ProtoCure | Herantis Pharma; | Cancer, bladder; Dermatitis, atopic; Psoriasis; Dry eye; Cystitis, interstitial |
| Phase II | LAS-41004 | LAS-41004, Betamethasone dipropionate/bexarotene | Almirall (Originator); | Psoriasis, plaque; Dermatitis, atopic | |
| Phase II | CC-90001 | CC-90001 | Celgene (Originator); | Fibrosis, pulmonary; Inflammation | |
| Phase II | 2-(3,4-Dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-1-benzopyran-4-one; 3,3′,4′,5-tetrahydroxy-7-methoxyflavone | XG-104 | XG-104 | Xigen (Originator); | Dry eye |
| Phase III | 2-(2,3-Dihydrobenzothiazol-2-ylidene)-2-[2-[2-(3-pyridyl)ethylamino]pyrimidin-4-yl]acetonitrile | AGI-1067; AGZ-1067 | AGI-1067; AGZ-1067, Succinobucol (USAN; Rec INN) | AtheroGenics (Originator); | Diabetes type 2; Restenosis, arterial; Atherosclerosis |
| Phase III | 3-[3-[2-(1-Piperidinyl)ethoxy]phenyl]-5-(1H-1,2,4-triazol-3-yl)-1H-indazole | AM-111; D-JNKI-1; D-TAT-IB1(s); XG-102 | AM-111; D-JNKI-1; D-TAT-IB1(s); XG-102, Brimapitide (Rec INN) | Auris Medical; Xigen (Originator); | Stroke, ischemic; Inflammation, eye; Reperfusion lesion; Hearing loss; Cancer |
Distribution of indications for JAK inhibitors
The first JAK kinase was discovered in the early 1990s, and it was not until 2012 that the first JAK kinase inhibitor-tofacitinib, was approved for the treatment of Rheumatoid arthritis (RA). RA is a chronic systemic autoimmune disease characterized by joint disease, which is characterized by persistent damage of the immune system to the joint and other tissues. Complex diseases are mediated by a variety of immune cells (B lymphocytes, T lymphocytes, macrophages, etc.) and related cytokines. Rheumatoid arthritis is known to cause a range of symptoms, including pain and swelling in the joints, especially in the hands, feet, and knees. Statistics show that there are about 4 million rheumatoid arthritis patients in China, the remission rate of patients is 8.6%, and the disability rate is about 50.3%. At present, tofacitinib is also used in a number of clinical studies with different indications, such as dry eye disease, Crohn’s disease, psoriasis, ulcerative colitis, and organ transplantation.
JAK inhibitor development pipeline
At present, the JAK inhibitors approved by EMA for FDA are Ruxolitinib, Tofacitinib, Oclacitinib, and Baricitinib.
Ruxolitinib, an inhibitor of JAK1 and JAK2, developed by Incyte and Novartis, was approved by FDA in November 2011 and is the first drug approved specifically to treat myelofibrosis. Ruxolitinib is conducting a number of clinical trials in the middle and late stages, indications include a variety of cancers, rejection, alopecia areata, allergic dermatitis, rheumatoid arthritis, vitiligo, psoriasis, and so on.
Tofacitinib, an inhibitor of JAK3 and JAK1 developed by Pfizer and approved by FDA in November 2012. This is the first oral JAK inhibitor approved for RA therapy. Tofacitinib may lead to some adverse reactions, including infection, tuberculosis, tumor and liver injury, and some of these adverse reactions may be related to the lack of selectivity of tofacitinib to JAK-3. The European Medicines Agency Council of Medicines for Human use (CHMP) has not approved the drug for sale in Europe after considering the efficacy and adverse reactions of the drug in the treatment of RA.
Oclacitinib, is a new JAK1 inhibitor approved by the FDA in 2013 to control itching and atopic dermatitis caused by allergic dermatitis in dogs.
Baricitinib, is a selective inhibitor of JAK1 and JAK2. On Jan. 20, 2016, Incyte and its partner Eli Lilly announced that baricitinib had submitted a NDA application for the treatment of mild to severe rheumatoid arthritis. Clinical trials of the drug are currently underway for a number of different indications.
Conclusion
When the development of JAK inhibitors was just beginning, based on the understanding of the different biological functions of JAKs, the researchers predicted some characteristics of JAK inhibitors. With the development of large-scale clinical trials of JAK inhibitors, some of the original predictions have been confirmed, but some unexpected results have been produced, and some key questions remain unanswered. For example, there are questions as to what extent the selection performance of JAK inhibitors has been achieved, and is it really advantageous to have high selectivity? Perhaps some of the uncertainties in the development of JAK inhibitors will be resolved step by step as more new trial data become available.
References
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2. Murray, P. J. (2007). The JAK-STAT signaling pathway: input and output integration. The Journal of Immunology, 178(5), 2623-2629.
3. Yan, Z., Gibson, S. A., Buckley, J. A., Qin, H., & Benveniste, E. N. (2018). Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clinical Immunology, 189, 4-13.