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


Posted by kinasepro on September 15, 2007

Vertex’s Ph2 p38 inhibitor:


is described in WO/2007/103468; model below



24 Responses to “VX-702”

  1. Any thoughts on the stability of the urea? Have you seen structures in patents where the pyridine nitrogen is replaced with carbon and linked to the amide nitrogen with methylene?

  2. kinasepro said

    GSK has quite a few compounds that are close to what it is I think your describing. And it seems like everyone into p38 has some kind of bicyclic ketone/napthyridone analog waiting in the wings.

    On stability? Nope not a one (thought that is).

  3. milkshake said

    Ureas are fine metabolically – proteases tend to leave them alone. Alkyl substituted ureas get dealkylated, oxidatively by alpha CH abstraction.

    I think this is the typical Vertex design – small MW, no solubilizing side-chains, quite polar. I would be curious to see what their solubility and PK is – but I am not going to re-synthesize their clinical candidate in order to find out; I have not been doing p38 long time.

    I would be curious to know if they also have the sporadic hepatotoxicity issue that troubled all p38 compounds so far.

  4. JJ said

    It can be difficut to market a small-molecule drug to target p38. VX-680 is certainly a good candidate— it might not be because it inhibits Aurora as originally designed; it would be because it is potentially a good second-line drug candidate against CML.

  5. weirdo said

    Is VX-702 still even in development? I don’t think it was mentioned during the VRTX “pipeline update” in June, and the reported Ph.2a results from last year weren’t that impressive.

    “milkshake” implies he may be working on p38 now: Get out, dude, just get the hell out!

    Not sure what the reference to VX-680 has to with p38 . . . or marketing a small-molecule drug targetting p38. We’re likely never to know!

  6. milkshake said

    if you read my comment – I did get out, more than 2 years ago.

  7. moody blue said

    Not to nitpick milkshake, but VX-680 does have N-methylpiperazine, possibly a solubilizing group! Just thought I would drag VX-680 in here again!! ;))

  8. moody blue said

    Referring to GMC’s comment………….I think the pyridine nitrogen is important. It might be locking the carboxamide in a favorable conformation through intramolecular H-bond.

  9. kinasepro said

    They mentioned it in a July conferance call: (via seeking alpha)

    We are also advancing VX-702 for the treatment of rheumatoid arthritis. We’re conducting a 12-week Phase 2 clinical trial in approximately 120 patients with rheumatoid arthritis in the background of methotrexate.

    Enrollment as we complete, and we expect to update it from the Phase 2a study by the end of the third quarter. The results on the Phase 2a trial and the thorough QTc study, which is also underway, will determine whether we initiate a larger Phase 2 trial on the background of methotrexate.

  10. rosko said

    Based on 1MQ7?

    That’s the structure of a dUTPase from M. tuberculosis. I tried looking at structures of other inhibitors bound to p38 and couldn’t find anything chemically resembling this Vertex compound, so I don’t know where you got that from. It don’t doubt that it’s probably correct, though.

  11. milkshake said

    Vertex scaffold is a ring-disconected mimics of the Merck bicyclic scaffold (and so on). Roche and many others have now a similar stuff as Merck. AFAIK most of it was published and mothballed.

  12. kinasepro said

    Heh, There’s my dyslexia coming out again… Thanks for the correction Rosko. It should read 1M7Q

  13. PK said

    Cross talking of different targets or related compounds in
    a certain context is interesting and helpful. Compared to
    c-Abl, P38 is a black hole for burning money. As VX-702 is
    not necessary to stick always on p38, VX-680 came out
    against Aurora kinases, but might end with c-Abl. Since
    you folks already mentioned Vertex compounds above, I
    posted up a question below for JJ, milkshake or weirdo
    [you sounded like a kinasefighter rather than a kinasepro;
    do not throw a stone at me :–) ]: what ‘s the rationale for
    VX-680 to be potentially a good drug for c-Abl (I guess,
    resistant mutation related); how compared to dasatinib
    then ? [kinasepro may move this discussion to somewhere
    esle if you like.]

  14. milkshake said

    VX-680 maps up quite nicely on Dasatinib, known Src/Abl inhibitor from BMS. I think KinasePro had a post on it few months back.

  15. JJ said

    Dasatinib does not work for the notorious T315I resistant mutant of c-Abl;
    VX-680 seems ok.

  16. kinasepro said

    everybody was kinase-fightayyaying

    (baddabaddba bumbum bombom bahm)

    those cats were fast as lightneeheeyeen

    (baddabaddba bumbum bombom bahm)

    in fact it was a little bit frightnayyayang

    (baddabaddba bumbum bombom bahm)

    but they fought with expert timeeyeeng…

  17. PK said

    The T315I mutation in c-Abl is the toughest as far as I know.
    No second-line drug has emerged yet. That would be a big
    milestone in anticancer therapy if the compound works via
    shutting down the mutant. But …..should VX-680 be better
    than Dasatinib as they match each other quite well in binding
    as milkshake mentioned, again, rationale?

  18. kinasepro said

    I wouldn’t say they match, but they do overlay in an interesting way.

    As far as rationale goes, both VX-680 and Dasatinib are multi-kinase inhibitors. They each hit all sorts of things, just different subsets of all sorts of things…

  19. moody blue said

    While looking at your overlay, I had this thought. How valid is it, let the experts decide. VX-680 has an extra H-bond (donor) contact with the hinge region compared with Dasatinib. Even if one were to invoke that controversial C-H H-bond donor, it would be much weaker than pyrazole’s N-H in VX-680. Now, is that additional H-bonding making VX-680 better against mutated tumors??
    The reason for my thinking is that I remember from another discussion involving Vertex & JnJ c-Met compounds. Milkshake had mentioned Sugen’s triazine scaffold (which is the forerunner of the Vertex & JnJ compounds, IHMO) did not work well against certain mutated tumor cell-lines, while Sugen’s aminopyridine scaffold worked on a more broad level. The link here is while the triazines (and the Vertex & JnJ c-Met compounds) have only ONE H-bond (acceptor) contact, the aminopyridines have TWO, a donor and an acceptor. May be that extra contact more efficacious against mutations??
    Apologies to KP and others if confused everyone and caused the present discussion to drift further :((

  20. PK said

    Far from convinced. T315I is the toughest play of a malevolent shedim. Wake up! JJ, milkshake or …any Vertexer underwater?

  21. milkshake said

    I have no interest in Vertex, I have seen shome shitty patents from them (=full of prophetic examples) but I like their design.

    (The only underwater options that I ever had was what I got from working at Pharmacia. After the merger the stock options were converted into Pfizer options; and soon after the Pfizer share prices nearly halved .)

  22. kinasepro said


    I think its pretty well known that its the amide NH in dasatinib forms a hydrogen bond to the threonine gatekeeper. But if anyone wants to talk more T315I though there’s a perfectly good thread next door for that…

  23. Been There before said

    primary ureas can be base and heat labile. this one in fact is and that is fact.

  24. binding said

    Vertex clinical trials used rather low doses, potentially tox-limiting. If so, the negative results don’t necessarily disqualify P38 as drug target.

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