Technology
JAK3 specific inhibitors
A new direction for JAK hopefuls
JAK3 specific inhibitors – A new direction for JAK hopefuls
Pharmacological targeting of the JAK1, JAK2, and JAK3 has proven to be efficacious in treating immune and inflammatory diseases; however, the lack of selectivity with first generation JAK inhibitors has been associated with significant safety concerns.
Most JAKs illustrate significant redundancy, being involved in several pathways. In contrast, JAK3 only transduces signals from γ-chain cytokines IL-2, -4, -7, -9, -15, and -21. Thus, it is expected that a drug that is selective for JAK3 should have relatively defined downstream effects, predominantly reducing the activity of γ-chain cytokines.
Differentiating JAK3 inhibitors: Difficulties with specificity
Selective small-molecule inhibition of JAK3 is challenging due to the highly conserved ATP binding pocket within the Janus kinase family (JAK1, JAK2, JAK3). JAK3 has the most potential to be targeted for highly specific immunology and inflammatory indications. JAK3 has Cysteine residue (Cys909) instead of serine in the same position of the ATP binding site.
Next generation highly selective & potent JAK3 inhibitors have the potential to be differentiated from first generation JAK inhibitors which all have side effects associated primarily with JAK1 and JAK2. OR-101 is a JAK3 kinase ATP competitive inhibitor, and due to structural differences, can potentially be differentiated clinically on safety and tolerability.
Ornovi’s OR-101 is a dual JAK3/ITK inhibitor that binds covalently and irreversibly to Cys909. We believe the irreversible binding of OR-101 enables higher specificity and selectivity, leading to a potentially safer profile than the first generation JAKs (various combinations of JAK1, JAK2, JAK3).
A differentiating aspect of OR-101 is the ITK inhibition. ITK is a subset of the TEC family. The TEC protein tyrosine kinase includes five members – TEC, BTK, ITK, BMX, and TXK. TEC family non-receptor tyrosine kinases are expressed primarily in hematopoietic cells and serve as important mediators of antigen receptor signaling in lymphocytes.
ITK is involved in T-cell receptor signaling. Currently, only ITK has been found to have a clearly defined function in T cells, leading to the conclusion that ITK is the predominant TEC kinase in T cells. In contrast, BTK is essential for B-cell receptor signaling because mutations in BTK are responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. It has been hypothesized that inhibition of the BTK, BLK, ERBB2 kinases may be responsible for most of the severe side effects arising from the inhibition of the TEC family. We believe that the selective inhibition of ITK instead of the entire TEC family may lead to a better side effect profile for OR-101 compared to current marketed JAK therapies.
Targeting JAK3-ITK
JAK3 Mediated Inflammatory Signaling1
ITK Mediated T Cell Activation2
1. Rochman et al. 2009 Nature Immunology; 2. Weeks et al. 2021 iScience
Targeting JAK3-ITK
JAK3 Mediated Inflammatory Signaling1
ITK Mediated T Cell Activation2
1. Rochman et al. 2009 Nature Immunology; 2. Weeks et al. 2021 iScience