Research and Development of Janus Kinase (JAK) Inhibitors


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

1. Rawlings, J. S., Rosler, K. M., & Harrison, D. A. (2004). The JAK/STAT signaling pathway. Journal of cell science117(8), 1281-1283.

2. Murray, P. J. (2007). The JAK-STAT signaling pathway: input and output integration. The Journal of Immunology178(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 Immunology189, 4-13.