janus kinase

PART 1: INTRODUCTION TO JANUS KINASES

Section 1: Aims of the Lecture (Page 1)

By the end of this lecture, students will:

• Gain an introduction to Janus Kinases (JAKs) .

• Understand the JAK-STAT signalling pathway.

• Understand the role Janus Kinases play in inflammation.

• Understand the mechanism of action of key inhibitors.

Section 2: What Are Janus Kinases? (Page 2)

2.1. Definition:

• Non-receptor tyrosine kinases (nRTKs) – they function within the cell cytoplasm rather than on the cell surface.

• They play a crucial role in the signalling pathways of various cytokines, growth factors, and hormones via phosphorylation and activation of target proteins.

2.2. Naming:

• Named after the Roman god Janus, who is depicted with two faces, symbolizing their dual functionality.

2.3. Structure:

• JAKs have two near-identical phosphate-transferring domains:

  • Kinase Domain: Responsible for the enzyme's catalytic activity.

  • Pseudokinase Domain: Regulates the activity of the kinase domain.

2.4. The JAK Family:

• There are four members in the JAK family:

  • JAK1

  • JAK2

  • JAK3

  • TYK2 (Tyrosine Kinase 2)

Section 3: Biological Roles of JAKs (Page 3)

Section 4: Clinical Relevance of JAKs (Page 4)

Dysregulation of JAK-STAT signalling is implicated in several diseases:

PART 2: THE JAK-STAT SIGNALLING PATHWAY

Section 5: Overview of the JAK-STAT Pathway (Pages 5-6)

5.1. Definition (Page 5):

• The JAK-STAT (Signal Transducer and Activator of Transcription) pathway is an important signalling pathway from outside the cell to the nucleus, regulating many cellular functions.

• JAKs represent the principal initiators of the JAK/STAT pathway.

• The pathway not only regulates cytokine signalling but is also implicated in the production of anti-inflammatory cytokines.

5.2. Mechanism of Action (Page 6):

Image Description (Page 6): A diagram illustrating the JAK-STAT pathway showing:

• Cytokine binding to receptors

• Receptor dimerisation

• JAK phosphorylation

• STAT binding and phosphorylation

• Translocation to the nucleus

• Gene transcription

Source: Pharmaceutics 2022, 14, 1001.

PART 3: JAK INHIBITORS

Section 6: Generations of JAK Inhibitors (Page 7)

Section 7: Classification of JAK Inhibitors by Mechanism (Pages 8-9)

7.1. Reversible JAK Inhibitors (Page 8):

• Reversible binding to amino acids in all 4 JAKs via hydrogen bonding and hydrophobic interactions.

• ATP Competitive Inhibitors:

  • Type I: Bind to the ATP binding site.

    • Filgotinib: Selective JAK1 inhibitor.

    • Fedratinib: Selective JAK2 inhibitor.

    • Tofacitinib and Peficitinib: Block multiple JAKs.

  • Type II: Bind to the ATP-binding site of the kinase domain in the inactive conformation of JAKs.

    • NVP-BBT594 and NVP-CHZ868: Target JAK2 (research compounds).

• Allosteric JAK Inhibitors:

  • Small molecule inhibitors that bind to a site other than the ATP-binding site.

  • Deucravacitinib (BMS-986165): Selective allosteric inhibitor of TYK2.

7.2. Irreversible JAK3 Inhibitors (Page 9):

• Form covalent bonds with a specific cysteine residue (Cys909) in JAK3.

• Chemical structure includes a covalent-bond forming group such as acrylamide or α-cyanoacrylamide.

• Ritlecitinib: Inhibitory activity mediated by covalent interaction with Cys909 residue in JAK3. Currently in clinical trials.

PART 4: JAK INHIBITORS APPROVED FOR CLINICAL USE

Section 8: List of Approved JAK Inhibitors (Pages 10-11)

Reference: J. Med. Chem. 2021, 65, 1047–1131.

PART 5: PROBLEMS AND SIDE EFFECTS OF JAK INHIBITORS

Section 9: Adverse Effects (Page 12)

SUMMARY TABLE: JAK INHIBITORS BY TARGET AND INDICATION

SUMMARY TABLE: MECHANISM CLASSIFICATION

KEY CONCEPTS

• JAKs are non-receptor tyrosine kinases that function in the cytoplasm.

• The JAK-STAT pathway is a key signalling pathway from the cell surface to the nucleus, regulating immune responses, cell growth, and haematopoiesis.

• Dysregulation of JAK-STAT signalling is implicated in autoimmune diseases, cancers, and inflammatory diseases.

• JAK inhibitors are classified by:

  • Generation: First (non-selective) vs. Second (selective)

  • Mechanism: ATP-competitive (Type I/II), allosteric, or irreversible/covalent

• Side effects include infections, GI perforations (with NSAIDs/steroids), increased LDL cholesterol, and cytopenias.