In the conference on kinase inhibitors I attended recently, there was a panel discussion on the second morning (why do these discussions have to start at 7:30 a.m.?) about the utility of selective vs multi- target directed inhibitors. The conventional wisdom has been that selective inhibitors- or any selective drugs for that matter- are best, since off-target effects can cause toxicity. The fight against cancer has largely been about finding selective and therefore safe drugs that hit targets only in cancer cells. It is a measure of how less we have accomplished in cancer therapy in spite of the countless amounts of dollars spent that we still are far from rationally designing reliable, selective and safe cancer drugs.
The discussion we had did not end in any consensus. While selective drugs may clearly be good in certain cases, there are cases in which drugs designed for selectivity ended up promoting their action by being non-selective and targeting multiple targets, but only in retrospect. Gleevec, the revolutionary drug for treating chronic myeloid leukemia, is a classic example. Initially supposed to be a "magic bullet" that targeted only a mutated kinase named Bcr-Abl in cancer cells, Gleevec later turned out to also potently target two other kinases, c-Kit and PDGFR. Interestingly these two targets are valuable targets in cancer therapy of two other cancers, renal cell carcinoma of the kidneys and glioblastoma of the brain.
In any case, the consensus was that we are still far away from designing drugs for a specifically chosen subset of targets. Something like staurosporine that hits almost every kinase out there is going to be undoubtedly gratuitously toxic. But inhibitors hitting a very specific subset of kinases could target a few crucial choke-points in disease pathways, thus serving as valuable drugs. But we are still far from rationally designing such inhibitors. Indeed, in the first place we don't even know what specific subset of kinases to hit for treating a particular disease. First comes target validation, then modulation. Most of the specific subset targeting kinase inhibitors seem to be discovered only in retrospect. In my own project where we are trying to target only one kinase selectively, we are now being skeptical about whether the beneficial effects we are observing are due to multi-target binding.
The other unrelated point we discussed was whether anybody knew kinase inhibitors which were near clinical trial phase completion for areas other than oncology. The silence around the table spoke for itself.
The bottom line is; as far as targeting specific subsets of kinases with inhibitors or even knowing which specific subset to target is concerned, we are still in the Stone Age of kinase drug discovery. The drugs which we have are largely still stone and tree branches. We have a long way to go before discovering tools and bronze.
In the next post, I will talk about a recent effort that overcame the rational multi-kinase inhibitor design for two very different kinases. It points the way forward.
Friday Fabulous Flower - winter thaw edition
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