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

PDB Update

Posted by kinasepro on September 18, 2007

Big week

2QOH; PPY-A bound to Abl via Ariad; Chem Biol Drug Des
2Z60; PPY-A bound to T315I Abl


(compounds from SGX)

2OH4; Benzimidazole bound to VEGF via GSK JP; J Med Chem

2V7A; PHA-739358 bound to T315I mutant of Abl via Nerviano; Cancer Res

2IN6 Wee1
2IO6 Wee1


5 Responses to “PDB Update”

  1. PK said

    Any compound potently to hit the ATP binding site is able to thwart the gatekeeper resistant mutation. The key for further development is then the selectivity and its related toxicity issue.

  2. kinasepro said

    Dasatinib pretty conclusively proves both points of your statement incorrect.

  3. PK said

    My comment is at a general ponit. If you understand correctly, Dasatinib is not able to overcome I315T resisant mutant and (because) its clorophenyl group binds into the deep pocket which is not in the ATP-binding site . The potent compounds thwarting I315T mutant would be more promiscuous than Dasatinib generally (Note: Generally) and more challenging for development.

    This is also the reason that it would be a big milestone (also for kinasefighters) in the anticancer therapy if VX-680 works for the mutant
    but still clinically tolerant. If so, it would be proven at the endpoint of Phase II.

  4. JJ said

    The T315I (gatekeeper) mutation shuts the door for Gleevec, Sprycel
    etc to intrude into the deep non-ATP contact pockets. Targeting the
    ATP site is a follow-up approach to overcome this mutation resistance,
    but being obviously confronted with the more challenging selectivity-related
    issue. However, it would still be doable. In deed, Sutent is the first small-
    molecule drug (with significant promiscuity) thwarting the gatekeeper
    mutation in c-Kit resistant to Gleevec. Other options to reduce the
    selectivity burden include binding a compound to an allesteric site or
    other related proteins (Hsp90, for instance), etc. Nevertheless, at this
    level of strategies, human beings would always fall behind in the battle.

  5. Pablo said

    I guess PHA-793358 is more advanced than VX-680….

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