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

Hey C&EN

Posted by kinasepro on August 20, 2007

Nice cover story on c-Met and thanks for link. Have a look around and don’t miss the perennial favorites:

The KinaverseKinase drugs & the Phase III compounds

6 Responses to “Hey C&EN”

  1. ExeFan said

    While ArQule’s lead compound binding into the ATP site of c-MET, Exelixis’s
    XL-880 seemly behaviors significantly differently. Exelixis’s structure could
    be a great one or could be a joke! They should have published their structure in a journal or PDB. I am wondering if Dr. Lisa Shewchuk @ GSK should make some comments on this in their recent reviewing the GSK-Exelixis deal invovling this compound.

  2. kinasepro said

    I’m at a loss as to understand this bit about the Arqule c-met compound:

    “We believe that ARQ197 may be binding to a part of the Met receptor that is close to the ATP-binding site, but it is clear from a number of preclinical studies that it is not competitive with ATP,” says Stephen A. Hill, ArQule’s chief executive officer.

    if the compound is as described by the red blobs in the first image which looks a lot like what I’ve suggested here… Then how could this compound be a non-atp competiive inhibitor?

    XL-880 is almost certainly from this vintage of quinoline, the only unresolved question is which group is in the solvent region.

  3. Wijit said

    I am not entirely convinced from the presentations by the ArQule team that the efficiacy demonstrated by ARQ197 can be attributed to inhibition of c-MET. I believe it is only a weak inhibitor of c-MET and thus it’s efficacy needs further explanation. Any further insight welcome …..

  4. ExeFan said

    The kinetic behavior of a compound can be non-ATP competitive ( assume we have the same concept) even if it binds into the ATP site, but, which must be in an inactive state.

    I’m really curious about how XL-880 binds in a mode similar to Gleevec (from the figure). If so, some conformational chane could occur in the hinge motif of c-Met like Tie-2? Anyway, it would help their business if Exelixis would publish the X-ray strucrure.

  5. kinasepro said

    Wij: At asco they claim it’s selective for c-met, but if ARQ-197 is the compound that I think it is… Right now this is just an if – but that is the structure they did the prodrug scan on, and the image in C&EN doesn’t cast doubt on this. Well… in the absence of data to the contrary it’s easy to speculate how it – or an active metabolite could be hitting all sorts of kinases. Of note Lilly has a BMCL from ’04 on a series differing by only one bond, and they describe the series as CDK inhibitors. (notable because its not outside the realm of possibility that the ArQule compound could reveal one of those in vivo as a metabolite.)

    XF: Your first statement on atp-competitive behavior: If I undesrstand you correctly your describing a partial agonist? I’m still filing the CEO statement into the does-not-computerate folder. On XL-880 it’s dfg-out and hits a lot more then just c-met. A subtle point, but I think the binding motif is more like Nexavar then Gleevec.

  6. ExeFan said

    No, antagonist. Generally speaking, ATP binding kinetics is also coupled, thus, complicating the overall kinetics of an inhibitor binding into an inactive state. This is also called indirect competition. In some special case like in MEK1-2,
    ATP and an compond (e. g. PD xxxxx) can co-exisit in the inactive pockets, coupled very weakly in kinetics. Other examples include a compound binds to an autoinhibition state where ATP binding does not significantly matter.

    Nexavar binds the DFG-out pocket in the similar mode to Gleevec, where
    actually my qestion came out—-The DFG-out conformation of c-Met
    is relatively high-energy state compared to that of c-Kit, c-Abl even
    and B-Raf. If XL-880 binds in the Nexavar’s fashion, it have to pay pretty
    much penalty from its binding free energy (my estimation was ~12.0
    kcal/mol !).

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