KinasePro

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

WO2006101937

Posted by kinasepro on October 5, 2006

Hi Janssen Pharmaceutica,

Nice c-Met application. This is one of those ‘hey didn’t Sugen already do this stuff?’ oxindole patents (Sugen: WO2005005378). The Sugen application focuses on the different regioisomer though. They also fairly conservatively claimed the H2 aryl’s. Anyways, the
hydrazones certainly do have both style and grace but the Jannsen application leaves Kinasepro wanting more. Kudo’s for working so close to Sugen’s matter, otherwise no soup for you.

Here’s a gratuitous hydrazone bound to CDK: 1KE6 (The carbon analog 1ke5 binds identically)


And here’s a gratuitous review on the c-Met as a target

c-Met pdb’s:

1R0P
1R1W
2G15

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4 Responses to “WO2006101937”

  1. milkshake said

    I was on this project at SUGEN. These acylhydrazones have realy lousy PK because the acyl on the isatine hydrazone is very hydrolyticaly unstable. They are also pretty insoluble unless you put a substituent ortho to the oxindole NH. We managed to find a good hydrazone isoster and changed the scaffold to tetracyclic and then to bicyclic compounds that were more potent and much more drugable than the starting hydrazone. (At that point Pfizer shut us down). I think our patents on the tetra- and bicyclic isosters should be out by now.

    By the way, your picture of the binding mode is not correct, we got a co-crystal and the hydrazones bind in a non-typical mode, very different from the usual oxindole stuff.

  2. kinasepro said

    >>By the way, your picture of the binding mode is not correct, we got a co-crystal and the hydrazones bind in a non-typical mode, very different from the usual oxindole stuff.
    Fascinating !

    See I knew there was a reason for Kinasepro to start this blog – Much less to profess his knowledge of everything, and much more to meet interesting people and learn new things.

    That picture is an aryl hydrazone from the CDK co-crystal 1ke6. Kinasepro otherwise assumed that the acylhydrazone would bind to c-Met quite similar.

    1r0p is a a published structure of a staurosporine analog bound to c-met and it binds as staurosporine always does. The interesting thing about 1r0p is that DFG and the activation loop is in quite an unusual configuration. The polar contacts are still as expected though.

    I’ll look at some overlays tonight and post them up –

  3. milkshake said

    I think I should not discuss the exact binding mode of these compounds in detail (ex-company lawyers could try to freeze my balls in Carbonite) but here are our hydrazone isoster patents:
    US 7,037,909 B2 (WO/2005/004808)and US Patent pre-grant 20050014755 (Provisional 60/484,222, filed Jul. 2, 2003)

  4. sureshg said

    Lovely blog and I really enjoyed visiting your blog!

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