KinasePro

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

WO/2007/075567

Posted by kinasepro on July 7, 2007

A reader comment got me to take a closer look at the titled JnJ application.  I don’t see it making their blog, but given its similarity to a recent a Vertex application of course it’s going to make this one.

FC(C1=CC(C=CC=N2)=C2C=C1)(F)C3=NN=C4N3N=C(C5=CN(C)N=C5)C=C4

1 nM autophos

 regression @ 25 mg / kg ?  Them some lucky mice.

clogp= 1.28 MW=377

Yah, I’d say your compounds are getting jealous right about now.

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16 Responses to “WO/2007/075567”

  1. Wijit said

    Nice one! Hats off to the boys and girls at J&J. Do you think one of the triazole lone pairs is binding to the hinge? Looks a bit unusual to me.

  2. milkshake said

    I think this is a close knock-off of one SUGEN c-Met series. If this is true then the quinoline is going deep into a pocket outside the binding site and the bicyclic core binds perpendicularly over the binding site, as a lid over a pot while pi-stacking with tyrosine in the activation loop. CF2 is put there because the benzylic methylene was a place of oxidative metabolism. The replacement of phenol with quinoline is a nice touch (the phenol in orig series was a H-acceptor) . Compare it with the best SUGEN c-Met compounds:

    PCT Int. Appl. (2005), 47 pp. CODEN: PIXXD2 WO 2005010005 A1 20050203

    The trouble with this series was that it was highly sensitive to site mutation in c-Met, lots of tumors has mutated c-Met and this class of compounds did not work for more then half of the known mutants. The other series (2-aminopyridines) were not sensitive to c-Met mutation. We had good metabolicaly stable compounds from the other series but not from this this particular series – we did not finish before we got Pfized down. So Agouron/Pfizer advanced the other series.

    Also, c-Met is not cytostatic as such, it works against spread and metastasis. I think xenograft on rodents is not the most reliable model to address tumor progression and development of resisance to a chemotherapy. I am not complaining but I think threre may be disappointing efficacy results later on.

  3. kinasepro said

    Thanks for the heads up on the Sugen series, I hadn’t seen that one.

  4. Wijit said

    Yeah, thanks for the heads up on the series. This was a real nice application from J&J …… their generic claims were well focused around the examples they made, not like some generic claims these days and the experiemental section was well described with good procedures and data. My wish is to see more applications of this quality in the future. Love & Peace, Wijit.

  5. jl said

    Very interesting. Any detailed description of the assay? Am just wondering this compound has not even one H-bond donor (the cMet hing has two H-bond acceptors).
    Could some N be protonated, anyhow? JL

  6. JJ-TTP said

    It seems to me that it is relatively hard to inhibit cMET (similar to IRK in this aspect) compared to EGFR. Normally, suitable hinge H-bonding contacts are required if a compound binds into the ATP-binding site of cMET only. Any in-house X-ray shows some interesting stuff? JJ-TTP

  7. xtallographer said

    two comments: 1) it’s real easy to achieve regression if you start your mice that early (Day 2 post implantation) and with such tiny tumors, & 2) this compound will clearly have a standard binding mode for c-Met inhibition…..(data unpublished) 🙂

  8. kinasepro said

    -J

    A click of KP’s sidebar c-Met link suggests people are going after c-Met with some new twists on the usual suspects – Staurosporine analogs, pyrimidine bicycles, acyl-ureas attatched to quinazolines and the like…

    This discussion certainly has me looking at the Merck series in a new light though.

  9. JJ said

    Good points, folks. But, xtallographer, would you pls expand (2) a bit more? Does a standard binding mode mean a H-bond to the hinge or other novel conformation determined in X-ray ? JJ

  10. Biotech said

    I understand the CF2 group being there to avoid benzylic oxidation at this position but can the fluorines be involved in binding as well… like JL said, there’s only one H-bond acceptor in the molecule, which isn’t unusual but for something so potent, I’d have expected at least a donor there!

  11. milkshake said

    I dont believe the X-tallographer saying the compound is a classical binder. We started with X-ray of isatine hydrazone bound to c-Met. These hydrazones had bad stability. I found a tetracyclic isostere that perfectly overlays with these hydrazones and the SAR was perfect match also. It is just little too insoluble and ugly. But a disconnecetion of the second ring of this abominable tetracycle produced even more potent series – it is the series on which J&J compound is based. I think it is unlikely that the binding mode changed in the process. I think X-tallographer probably works for J&J and is pissed that I am discussing this stuff.

  12. kinasepro said

    “…clearly have a standard binding mode for c-Met inhibition…”

    No reason for anybody to be pissed, if JnJ had anything to hide they wouldn’t have put so much data in the application. And well, X- did qualify that with a ‘for c-Met’! I gather that those in the know already knew…

  13. xtallographer said

    Then again, I could be wrong…..it happened once before…… 🙂

    BTW, I never said “classical”….that would be the old donor:acceptor pair with a big hydrophobe. I said standard for c-Met (as kinasepro noticed)…..and I suppose perhaps it’s only standard to me…..

  14. JJ said

    Xtallographer, Thanks a lot for the response. It is always good to get some echo.., although I am quite confused by ‘standard for c-Met…’—-I do not think c-Met is so special in the protein kinase family members.

    X-, would you pls say st about the function of N in the quinoline in the J&J compound?
    I have similar feeling of bow the compound binds into c-Met, however, I could not figure
    out why the compound is so potent….Thanks, again. JJ.

  15. coah-K said

    I agree with JJ …I do not beleive the listed J&J compound is 1nM against c-Met either. But sometime it is a bit hard to comapare with assay data because of different assay settings from different experiments …. Coach-K

  16. coah-K said

    BTW, Dr. Roger Bone, Senior VP of J&J will give a keynote talk about
    ‘Surprises in Structure-based Drug Design’. You may ask
    him if you get a chance in ACSProSpectives, Sept. 9-11, Hyatt
    Regency Airport, San Francisco. …………..Coah-K

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