Kinase Inhibitors: beyond Oncology

We recently published a paper in Bioorganic and Medicinal Chemistry, targeting Interleukin-2 inducible T-cell kinase (ITK) for treating Asthma. 

Protein kinases are prime targets for anticancer therapies, but achieving specificity for a particular kinase is challenging because of their close structural similarities. This leads to unwanted side effects, and the toxic outcome may also be due to the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in treating both chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers but is associated with severe cardiotoxicity. Toxicity may be of less concern with oncologic kinases; what about non-cancer indications? Emerging clinical evidence (Nature Drug Discovery) of oral kinase inhibitors other than cancer shows that kinases could effectively inhibit the number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue. For example, SCIO 469 and Arry 797 initially developed for RA but went into the clinic for post operative dental pain; here, the potential toxicity problems will not show up because the drugs are used only for a very short time. Are BMS-582949 and VX 702 still in development? Different companies have spent hundreds of millions on P38 with nothing to show at the end.

Tasocitinib may be the first kinase inhibitor (JAK3) for non-oncology indication and the first oral DMARD for RA in a decade if it successfully completes Phase III clinical trials.

The rule 2-0

Recently, Aronov from Vertex pharmaceuticals proposed a general ‘rule of thumb’ termed the 2-0 rule for kinase likeness to discriminating kinase inhibitors from the nonkinase molecules.

For kinase activity, the molecule should have

1) One or more heteroaromatic nitrogen’s,

2) One or more heteroaromatic NH group,

3) It contains one or more aniline, and 

4) It contains one or more nitriles.

Around 78% of the kinase compound passes the 2-0 rule.

Are Protein Kinases Drug Targets?

Kinases catalyze the transfer of phosphate groups from phosphate-donating molecules (like ATP) to other molecules. They have been intensively investigated as drug targets for many years. Around 20-25% of the druggable genome consists of kinases, and this target accounts for 20-30% of many companies' drug discovery programs.

Several protein kinase inhibitors have been approved by FDA and available in the market which includes Tykerb®, Sprycel®, Sutent®, Nexavar®, Tarceva®, Iressa®, and Gleevec®. Many other kinase inhibitors are currently undergoing clinical development. This accelerated the research and development in this area, reflecting the number of search results for 'kinase inhibitors'. Sci-finder keyword search resulted in 1281 patents, which is filed in 2007 alone. Drug and Market Development’s (D&MD) report (2005) shows that kinase targeted therapies growing from $12.7 billion in 2005 to $58.6 billion in 2010. 

 

So what is the problem with kinases? The lack of selectivity for targeting a specific kinase is the issue due to the similarity of other kinase targets. For example, the natural product substrate Staurosporine hits almost every kinase out there will be gratuitously toxic. However, the real problem with kinase inhibitors is the toxic outcomes may result from tissue distribution of orally administered kinase inhibitors.

 

Kinases are drug targets. But, difficult ones.