KinasePro

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

Vertex and c-Met

Posted by kinasepro on June 12, 2007

A reader asks what’s up with these, which got me wondering the same. An interesting new c-Met application from Vertex (WO/2007/064797) likely stems from a screening hit off of a related GSK3 series: WO/2004/058769.

OC(C=C1)=CC=C1CC2=NN=C3N2N=C(NC4=CC=CC=C4)C=C3

There are a number of examples trying to get away from the phenol, things like prodrugging, and as many isosteres as you shake a stick at. A few interesting modifications appear to produce < 100 nM Ki compounds.

As for how they bind? Well… your guess is as good as mine, but here’s mine: (oops – it’s since come out that the phenol in this motif hits the hinge. so this was a cute idea but wrong)

oops

Just what’s up with the phenol? I have some ideas, but its kind of tricky to guess given the mobility of the a-loop.

Advertisements

6 Responses to “Vertex and c-Met”

  1. sks said

    Is there a problem with a free phenol?

  2. kinasepro said

    Only if protein binding, glucuronidation, and poor permeability bother you…

  3. sks said

    thx

  4. milkshake said

    Yeah, this is completely based on sugen patent

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

    which was based on tetracyclic compounds from sugen patent

    PCT Int. Appl. (2005), 73 pp. CODEN: PIXXD2 WO 2005004808 A2 20050120 CAN 142:155983 AN 2005:55025

    which was based on earlier isatine hydrazone sugen patent

    PCT Int. Appl. (2005), 189 pp. CODEN: PIXXD2 WO 2005005378 A2 20050120

    which was based on high-throughput hit from screening Kalamazoo compound collection

  5. milkshake said

    I should add that your binding mode is wrong, the explanation of how it binds is in the comment on today’s J&J post.

  6. kinasepro said

    no cookie for me

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

 
%d bloggers like this: