Kinase Chemistry – Just a year and a half behind the times.

J Med Chem Review

Posted by kinasepro on January 10, 2007

If you subscribe to the J Med Chem feed, you’ve probably already seen this ‘perspective’. May I just say that rarely does a journal article have such a deep impact on me, but this one really shakes it up.

First thing I noticed was that he got the structure for Gleevec wrong. That right there told me to stop reading… But hey, where’s the fun in that?

Since some goofeballs actually read this blog, maybe I should be nice… Hmm….. Nah. Welcome to the internet age where you submit a halfbaked manuscript to a major journal and we prepare the flames.

None more then KP appreciate a good discussion on structural biology and kinase inhibitors, and I respect what the author is trying to accomplish here. It’s exceedingly difficult to represent and discuss a 3D model on 2D media. Being the managing editor of KinasePro I’ve experienced this first hand.

On the structures: “Triazolopyrimidine derivative (24)“: Wrong tautomer? Extra atoms? Missing Bonds? Wrong compound. “Compound 18 (AP23464)“: missing a bond. dasatinib is bis-protonated? purvalanol a is isopropyl not t-butyl, and of course in Gleevec the piperazine should be para not meta.

You could argue all this is really just book-keeping. More important is the content, and on that topic I have less to say. Perhaps this ‘perspective’ will further advance someones understanding of how inhibitors bind to kinases, maybe it wont, but doesn’t there come a time when during the course of the manuscript preparation you just have to take a step back and say…

this looks like crap ?

This (free link) article does a better job on the topic, but frankly there are subtleties that 2D and even 3D will just not access. Kudos to the author for approaching a difficult topic. Shame on J Med Chem for not properly rejecting reviewing this offering. Oh, and Duke sucks.

>> Update 2/1/07 >> It looks as though J Med Chem finally made the corrections pointed out above. It will be interesting to see if the errors made it to print. I’m still not convinced (24) is the correct structure though.


12 Responses to “J Med Chem Review”

  1. weirdo said

    What do you want, the dude works for TransTech. Seriously. And ORTEPS don’t show bond order, so how was he supposed to know?

    And, frankly, I resent being lumped in with those individuals whom you consider “goofeballs”. I will assume you are only referring to milkshake.

  2. milkshake said

    Even if the guy got his structures right – I think no-one should take seriously a review that is trying to summarize the common features of all kinase inhibitors.

    If he for example illustrated four distinct ligand binding modes for some important kinase – and maybe contrasted this with the situation in another closely related kinase (and maybe highlighted some differences between the two that could provide for more selective inhibitor design) then I think we would get some useful read out of it.

  3. kinasepro said

    Yah, but its J Med Chem? Did no one read it before they stuck it in the February issue? I find it a little peculiar that it was submitted last July, but didn’t appear on ASAP.

  4. milkshake said

    It is in the ASAP online release right now, so perhaps it will go into the April 1st issue…

  5. Derek Lowe said

    If someone called me and invited a review on general binding features of kinase inhibitors – all of ’em – I’d run screaming into the distance. Which is what this guy should have done, by the look of it.

  6. Joe said

    Great link (“duke sucks”) to the YouTube Video.

    Oh yea, the chemistry was interesting as well. I wonder if reviewers/editors are as knit-picky as they should be.

  7. Wavefunction said

    Derek; True, but Shokat’s review on features of selective kinase inhibitors is not bad at all. Search Chemistry and Biology.

  8. kinasepro said

    Here’s another free article on this topic from the open access journal Arkivoc.

  9. kinasepro said

    and another from J Med Chem:

    ‘Toward a Pharmacophore for Kinase Frequent Hitters’

  10. John Harris said

    Take a look at Current Medicinal Chemistry, 2006, p.1735 and references (especially ref 34 and ref 36) cited therein for much simpler and, I would suggest, much more useful views of the relationships between kinase inhibitors.

  11. kinasepro said

    Thanks for the tip.

  12. John said

    I would view this paper would be one of the best review papers in the kinase
    field in the recent decades because of its correlating the target structures with the types of potent small-molecule inhibitors and their binding modes; especially, the conformational changes driving the changes of small-molecule binding and their potency. The later is still a challeging problem in the kinase drug design (as well as others)—particularly for those protein kinases whose structures not yet available.

    To my understanding, Fig. 13 listed above tried to capture the real (3-D) binding
    mode in the 2-D representation—so it does not look exactly like a chem-draw structure; I would look at this represntation for binding modes in a postive way–
    it shows (more clearly than 3-D) how a compound interacts with the pockets and
    would help medicinal chemists to figure out how to design a compound; this is difficult to achieve to just look into a 3-D structure. In addition, I would think this
    type of presentation would be as important as a 2-D structural formular for a
    molecule in the field of design.

    Just a thought. John

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