clinical cancer drugs identified as inhibitors of inflammatory signaling
Leucemia mieloide cronica (LMC) (credit: https://commons.wikimedia.org/wiki/File:Chronic_Myeloid_Leukemia_smear_2009-04-09.JPG by Paulo Henrique Orlandi Mourao via Wikimedia Commons is licensed under CC-BY SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0/deed.en)

Imatinib (sold as Gleevec) is a breakthrough cancer drug approved in 2001 for the treatment of Chronic Myeloid Leukaemia (CML).  It was designed to inhibit the BCR/ABL fusion protein, a constitutively active version of the kinase ABL, that was found to be responsible for 95% of CML cases. Imatinib proved to be extremely effective, but eventually, the BCR/ABL protein would develop a mutation that would render it resistant to imatinib.

To combat this, several second-line drugs have been developed to target the resistant forms of the cancer. One of these is ponatinib, which was designed to target the T315I mutant form of BCR/ABL. When imatinib was originally developed, it was considered to be an extremely specific inhibitor, and that this was the reason for its excellent safety and efficacy profile.

Subsequent work has revealed that imatinib is not nearly as specific as was once thought, and actually has a wide range of off-target effects. Many of these may even contribute to its effectiveness as a cancer treatment. Ponatinib is far less specific even than imatinib, exhibiting a huge range of off-target effects that result in some severe side-effects. Ponatinib was approved by the FDA for the treatment of CML in 2012 but revoked the approval in late 2013 because the side effect profile of the drug was so bad. It was re-approved in early 2014 with additional warnings and restrictions on its use.

RIPK2: A Key Part Of The Signaling Pathway

In a recent paper, we discovered that ponatinib is also an extremely potent inhibitor of a kinase called RIPK2. RIPK2 is a key part of the signaling pathway that detects invading bacteria and activates the inflammatory response. The NOD receptors, NOD1 and NOD2, detect bacterial compounds and activate RIPK2. This causes RIPK2 to undergo two modifications: auto-phosphorylation, and ubiquitination by an E3 ligase. RIPK2 then triggers a signal cascade that results in the activation of two pathways, the MAP-kinase and NF-κB pathways, which both trigger the inflammatory response to fight the bacteria. Deregulation of this pathway can lead the development of several inflammatory conditions and cancers, so RIPK2 is considered a very promising drug target.

We screened for inhibitors of RIPK2 and ponatinib immediately stood out as being far more potent than any of the other drugs we tested. We used the stabilizing effect of ponatinib to help us crystallize the RIPK2 protein. This allowed us to solve the first ever crystal structure of RIPK2. The structure also showed how ponatinib interacts with RIPK2 and acts as such a potent inhibitor. Using this information we were able to predict that two similar inhibitors, regorafenib, and sorafenib, would also be inhibitors of RIPK2. We tested the potency of all three drugs against RIPK2 and found this was true, but ponatinib was clearly the most potent. All three of these drugs are known as “type-II” inhibitors, which means that they inhibit their target kinase by binding to it and locking it into an inactive conformation.

We followed up these experiments by testing the compounds in cells and discovered that all three inhibitors caused a reduction in RIPK2 phosphorylation and reduced levels of NF-κB activity. This indicates that the inhibitors prevent RIPK2 from being activated and this shuts down the inflammatory signaling pathway. We also tested a “type-I” inhibitor called gefinitinib. “Type-I” inhibitors work by competing for the ATP binding site of the kinase. Gefitinib proved to be considerably less potent than the type-II inhibitors in cells, which suggests type-II inhibitors make better RIPK2 inhibitors.

Following on from this, we identified that our type-II inhibitors were able to prevent RIPK2 ubiquitination and block the production of several inflammatory proteins. We also showed that ponatinib is able to block the inflammatory response in primary human monocytes. Ponatinib had no effect on a similar inflammatory pathway that doesn’t signal via RIPK2, indicating that the response we observed was due to RIPK2 inhibition.

These results could form the basis for the development of a new treatment for various inflammatory diseases. It is possible that regorafinib or sorafenib could even be a treatment for certain conditions. It is unlikely ponatinib could be used in this way because it has such a bad side effect profile, and chronic inflammatory conditions require extended treatment. We have also helped to understand the effect of several cancer drugs in active clinical use.

This study, Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors was recently published in the journal Chemistry & Biology.

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