Field of Science

The name's bond - reversible covalent bond.

Fifteen years ago most people would have laughed at you if you told them kinase inhibitors would become such a big deal: the received wisdom at that point was that anything that competed with ATP for one kinase would just indiscriminately hit other kinases. While that is generally true, we have found over the intervening decade that there is a wealth of detail - type II motifs, allosteric binding, relatively straightforward residue selectivity etc. - that can be tweaked to provide selectivity. In one fell swoop Gleevec upended the conventional wisdom.

A similar kind of thinking existed for covalent drugs a few years back, and I think that field too is going down the fortuitous road that kinase inhibitors took and defying the naysayers. This year especially has seen a bonanza of activity related to the discovery and fine-tuning of covalent inhibitors. The most striking and unexpected development in the field however has been the finding that one can find reversible covalent inhibitors that engage a protein target long enough to provide useful efficacy: the pessimistic thinking that had prevailed so far was mainly based on the potent off-target effects potentially arising from irreversible inhibitors. That thinking was justified...just as the thinking that kinase inhibitors would be non-selective was justified in 1998.

Reversible covalent kinase inhibitors in particular have seen a lot of interest and publications this year, and it's especially gratifying for me as a computational chemist to see that that the field is benefiting from both experimental and computational approaches. Jack Taunton at UCSF (who has started a company to exploit such kinds of inhibitors) has been a leader, but there have been others. Just recently there was a joint publication from the Taunton and Shoichet groups which used covalent docking techniques to prospectively discover JAK3 inhibitors. Taunton has also done some interesting work with Matt Jacobson from UCSF to use computational methods to tune covalent warhead reactivity - this work would be especially useful in tailoring reversible inhibitors to suit the target. A group at Pfizer did some similar work. Meanwhile the discovery of irreversible inhibitors for other important targets also isn't dead: earlier this year Nathanael Gray's group at Harvard published a report on covalent reversible inhibitors for CDK7, for instance.

It remains to be seen - it always remains to be seen - how many of these leads can survive the rigors of the clinic and how general the field becomes. But the approach in general certainly seems to be coming of age, and I will be watching its development with great interest. Quite a bit of promise there and also a real chance to defy some naysayers, which is what scientists especially relish.

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