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

Archive for October 19th, 2006


Posted by kinasepro on October 19, 2006

Hi Vertex,

Nice JAK3 / CDK2 application. Kinasepro notices that you folks patent an aweful lot of compounds, and chemotypes. Keeps me busy, but I have to wonder how you’ll find time to develop all these things.

There have been innumerable CDK2 inhibitors enumerated, and Xrays described. JAK3 – hmm… not so much. Interesting to me if you guys actually found a scaffold that hits’m both, because of some key residue differences. (gatekeeper: met vs. phe, and a selectivity residue: cys909 vs asn322)

Anyhow cool fused-pyrazoles, I guess if you squint a little you could find some similarities with the Aurora kinase inhibitor: VX680

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Posted by kinasepro on October 19, 2006

A big wuzzup to my peeps representin in the big 48,

Umm, thats country code 48. Umm, well you see I mean, ahh nevermind. Hi AstraZeneca nice CHK1, PDK1 AND PAK inhibitors. KP won’t lie, he hasnt seen a whole lot of PAK or PDK1 inhibitors, but he’s sure they’ve been implicated in everything from breast cancer to the tooth fairy. Chk1 PDK1 have been around the virtual-block for a while now, and there’s quite a few Xray’s in the PDB. Nothing quite like what you’re up to here though, so I’m quite happy to be poking through your latest application:

I don’t have a real good guess on how it’s binding, if pressed I’d say the amide is likely hitting the hinge, the aryl is headed off into H1, and the piperidines are in the ribose region (Chk1 acid residue in white below, is also in PDK1).

->> mid-post update, I wasn’t very clear on the binding mode until I cracked open PDK1 bound to staurosporine (1OKY) and overlayed it. I’d say I’m a little more confident now:

It strikes me that I’ve seen the indole-carboxamide as a kinase active scaffold before – something in the IKK vein. I’ll have to look it up and update tomorrow. Nice app.

Hej då
>> update >> indeed WO2006034317 is a Glaxo UK, IKK application from March, 06. which itself appears to be a continuation of SKB WO2005067923.   


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