Janus kinases (JAKs) are critical for cytokine signaling pathways regulating immunity, inflammation, blood cell production, and growth. JAK inhibitors work by inhibiting JAK-STAT signaling. Ruxolitinib is approved for treating myelofibrosis and polycythemia vera by inhibiting JAK1/2. Other JAK inhibitors in development target JAK1, JAK2, JAK3, or multiple JAKs for diseases like rheumatoid arthritis, psoriasis, ulcerative colitis, and various cancers. Adverse effects include infections, low blood counts, and cardiovascular risks, requiring monitoring during treatment. Further research on JAK-STAT pathways may identify new drug targets and

1. Janus kinase inhibitors
Dr. Rajesh Boini

2. outline
• Introduction
• Classification
• Mechanism of action
• Uses
• Adverse effects
• Conclusion

3. Introduction
• Janus kinases (JAKs) are critical components of
cytokine signaling pathways which regulate
– immunity,
– inflammation,
– haematopoiesis,
– cell growth and development

4. JAK-STAT PATHWAY

5. • JAK family :
JAK1,
JAK2,
JAK3,
TYK2
• STAT 1-6

9. Negative Regulation

10. • Protein tyrosine phosphatases remove phosphates from
cytokine receptors and activated STATs.
• Suppressors of cytokine signalling (SOCS) inhibit STAT
phosphorylation.

11. • Protein inhibitors of activated STAT (PIAS), which also
act in the nucleus through several mechanisms.
• For eg, PIAS1 and PIAS3 inhibit transcriptional
activation by STAT1 and STAT3 respectively by binding
and blocking access to the DNA sequences they
recognize.

12. PATHOPHYSIOLOGY

13. • JAK2 is engaging with multiple cytokine receptors:
Erythropoietin receptor (EPOR),
Thombopoietin receptor (TPOR also known as MPL),
G-CSFR, GM-CSFR, IL-3R
• Recurrent acquired somatic mutation Valine-to Phenylalanine
substitution at codon 617 of pseudokinase domain of JAK2
(JAK2V617F)
• > 95% in PV
• 32-57% in ET
• 35-50% in PMF

14. • JAK2V617F mutation maps to the JH2 domain of JAK2.
• JH2 domain has significant homology to JH1 but lacks
catalytic activity, is believed to involve in autoinhibition
of JAK2 activity.
• Mutant JAK2V617F is constitutively activated,
independent of (and also hypersensitive to) its ligand, e.g.
EPO

17. CLASSIFICATION
JAK 1 JAK 2 JAK 3 JAK 1/2/3
Filgotinib Pacritinib Decernotinib Tofacitinib
Upadacitinib Fedratinib Daricitinib
Ruxolitinib
Peficitinib : Pan JAK ( JAK 1/2/3 and TYK2 inhibitor )

18. Hematological indications
INHIBITOR TARGET COMMENT
Ruxolitinib JAK1/JAK2 Approved for PV and MF
Pacritinib JAK2/FLT3 Thrombocytopenia(transient) ,
ICH, MI (PERSIST 1&2)
Momelotinib JAK1/JAK2 Effective in anemia
Peripheral neuropathy(ADR)
Fedratinib JAK2/FLT3 Wernicke Encephalopathy

19. • COMFORT 1&2 trial 42/48% (RUX 10mg BD) Vs Placebo 1/0
at wk 24&48 , (1º endpoint: ≤35% reduction in splenic vol.)
• symptomatic or severe splenomegaly in pts with DIPSS risk
intermediate 2 or high
• Established therapy with Ruxolitinib in MF and PV
• RUX used as pretransplant in MF
• Long term results available in MF and PV
• Insufficient data for therapy with JAK# in ET
• Future : Combination therapy

20. Rhematological indications
Rheumatoid arthritis
Tofa: 5mg BD ; 11mg XR OD
Bari: 2-4mg OD : EU
2mg OD only in TNF-IR : US
Upa : 6 phase3 RCTs (NEXT,MONO,BEYOND,SELECT
EARLY, COMPARE,CHOICE)
Fil : phase3 RCTs: FINCH 1,2,3

21. • Psoriatic arthritis
Tofa: 5mg BD ; 11mg XR OD : US
Upa : 2 phase3 RCTs
Fil : phase3 RCTs
• Spondyloarthropathy
Tofa: phase 2 RCTs
Upa : phase2 RCTs
Fil : phase2 RCTs
• Juvenile Inflammatory Arthritis: Tofa : phase 2 RCTs

22. Dermatological indications
• Psoriasis :
Tofa : 10 mg BD FDA approved
Bari : phase3 RCTs
Upa : phase3 RCTs
Ruxo: 20mg OD (topical)
• Atopic dermatitis :
Tofa: phase 2 RCTs
Bari : phase3 RCTs
Upa : phase3 RCTs
Ruxo: 20mg OD (topical)

23. Canine atopic dermatitis : oclacitinib approved
Chronic actinic dermatitis: Tofa –RCTs
Alopecia areata:
Tofa: phase 2 RCTs
Ruxo: 20mg OD (topical)
Bari : phase2 RCT
Others
Vitiligo
Erythema multiforme
GvH disease

24. Gastroenterology Indications
• Ulcerative colitis
Tofa: 5-10 mg BD (mod-severe UC)
( OCTAVE 1&2 after 8wks 17.6%Vs 6%
1yr f/u 59.4%Vs 41%)
Upa : phase2 RCT
Fil : phase2 RCT
• Crohn’s Disease
didn’t show clinical efficacy

25. Autoimmune disease
• SLE
Tofa : phase3 RCT
Bari & Fil : phase2 RCT
• 1˚ Sjogren’s syndrome
Tofa : eye drops –dry eye disease
Fil : phase2 RCT
• Dermatomyositis : Case reports with Tofa, Ruxo
• Giant Cell Arteritis : Bari : phase 1 RCT
• Early diffuse SSc : Tofa phase 1 RCT

26. Adverse events
• Infection (TB , Herpes Zoster reactivation)
• Anemia, leukopenia, thrombocytopenia
• Dyslipidemia and cardiovascular disease
• GI Perforation
• Malignancy (Lymphoma)
• Thromboembolic/DVT ?JAK2 related
• sporadic elevations in serum creatinine
• Acute renal failure
• elevations in transaminases

27. Conclusion
• Unique in oral admn, not a protein , works intracellularly
• Biggest risk : Herpes Zoster reactivation
CDC: Vaccinate pts ≥50y with recombinant shingles vaccine
• Although sustained activation of JAK-STAT signal pathway is
closely linked to diseases, development of diseases is the result
of multiple genetic anomalies that involve multiple steps

28. • Therefore, further research is needed to explore the detailed
mechanism of JAK-STAT signal pathway
• Designing specific inhibitors against these proteins will
undoubtedly bring new hope for the treatment of diseases
• In-depth studies of cancer signal pathways and drug targets
will open up broad prospects for human beings to eventually
overcome cancer

29. REFERENCES
• CMDT 2020
• Ann Rheum dis 2018
• Am J Physiol Gastrointest liver physiol 2019
• Lancet Oncology 2016
• Ganong’s Review of Medical Physiology 25th edition

30. THANK YOU