James Ozanne, an undergraduate student from the University of Bath working under the direction of Kristopher Clark, has discovered that, in addition to their anti-cancer properties, the drugs Bosutinib and Dasatinib also possess potent anti-inflammatory actions by switching off a family of enzymes called the SIKs. These findings suggest that Bosutinib and Dasatinib could potentially be re-purposed for the treatment of chronic inflammatory and autoimmune diseases.
A major focus in the Clark lab is to identify new ways to tackle diseases of the immune system such as rheumatoid arthritis and lupus. To this end, the lab recently uncovered a key role for the SIKs in promoting inflammation (PNAS 2012, vol.109 p.16986-16991). Treatment of macrophages with compounds that block the activity of these enzymes leads to a dramatic increase in the production of beneficial anti-inflammatory cytokines (IL-10, IL-1ra) and a suppression of toxic pro-inflammatory cytokines (TNFÃ_±, IL-12, IL-6). This dual activity of compounds that switch off the SIKs have made them attractive targets for the treatment of inflammatory diseases. Unfortunately, none of the currently available compounds have the required drug-like properties to test this idea.
James therefore sought to identify clinically-approved drugs that could block the SIKs, in addition to their main target. Many anti-cancer drugs switch off enzymes known as protein tyrosine kinases. The lab previously noticed that these enzymes share a special feature with the SIKs, which could allow some drugs to bind to members of both families. By testing a number of different anti-cancer drugs, James found that Bosutinib and Dasatinib could block the SIKs, thereby converting macrophages to an anti-inflammatory state. James was able to further show that the effects of Bosutinib and Dasatinib were the result of blocking the SIKs, and not protein tyrosine kinases, because he engineered macrophages to express a mutant of the SIKs that does not bind to these drugs and found that Bosutinib and Dasatinib could not switch this macrophage population to an anti-inflammatory state.
Our findings, in combination with the current use of Bosutinib and Dasatinib in the clinic and the observation that Dasatinib is effective at suppressing arthritis and atopic dermatitis in pre-clinical models, make us optimistic that drugs which selectively turn off the SIKs will be well-tolerated in human patients and be efficacious in the treatment of chronic inflammatory and autoimmune diseases. We propose that in the absence of such compounds, Bosutinib and Dasatinib should be considered for the treatment of debilitating inflammatory diseases, in particular, those diseases for which there are no reasonable current treatments.
Click here to access the complete article published in the Biochemical Journal.
A major focus in the Clark lab is to identify new ways to tackle diseases of the immune system such as rheumatoid arthritis and lupus. To this end, the lab recently uncovered a key role for the SIKs in promoting inflammation (PNAS 2012, vol.109 p.16986-16991). Treatment of macrophages with compounds that block the activity of these enzymes leads to a dramatic increase in the production of beneficial anti-inflammatory cytokines (IL-10, IL-1ra) and a suppression of toxic pro-inflammatory cytokines (TNFÃ_±, IL-12, IL-6). This dual activity of compounds that switch off the SIKs have made them attractive targets for the treatment of inflammatory diseases. Unfortunately, none of the currently available compounds have the required drug-like properties to test this idea.
James therefore sought to identify clinically-approved drugs that could block the SIKs, in addition to their main target. Many anti-cancer drugs switch off enzymes known as protein tyrosine kinases. The lab previously noticed that these enzymes share a special feature with the SIKs, which could allow some drugs to bind to members of both families. By testing a number of different anti-cancer drugs, James found that Bosutinib and Dasatinib could block the SIKs, thereby converting macrophages to an anti-inflammatory state. James was able to further show that the effects of Bosutinib and Dasatinib were the result of blocking the SIKs, and not protein tyrosine kinases, because he engineered macrophages to express a mutant of the SIKs that does not bind to these drugs and found that Bosutinib and Dasatinib could not switch this macrophage population to an anti-inflammatory state.
Our findings, in combination with the current use of Bosutinib and Dasatinib in the clinic and the observation that Dasatinib is effective at suppressing arthritis and atopic dermatitis in pre-clinical models, make us optimistic that drugs which selectively turn off the SIKs will be well-tolerated in human patients and be efficacious in the treatment of chronic inflammatory and autoimmune diseases. We propose that in the absence of such compounds, Bosutinib and Dasatinib should be considered for the treatment of debilitating inflammatory diseases, in particular, those diseases for which there are no reasonable current treatments.
Click here to access the complete article published in the Biochemical Journal.