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

Archive for the ‘Vertex’ Category

Some highlights…

Posted by kinasepro on November 28, 2007

GSK’s been looking at Plk1 for quite a while. Sure the structure was in an earlier application (March), but here it is better late then never. See: WO/2004/074244, WO/2004/087652, WO/2005/019193, WO/2007/030361, US20070010668, & US20070270437

AP-24534 In here? Earlier Ariad had a double bond wiggling around T315I, in WO/2007/133560 & WO/2007/133562 it’s a triple bond.

And Vertex has an interesting series of series of Rock inhibitors in WO/2007/133622. Ki is reported to be <100 nM and clean across the cyps.

Oh yah, and if your curious about Cyclacel’s Aurora inhibitor CYC-116, they’ve narrowed it down to 1 of 3 for you and they also give an in vitro panel in WO/2007/132220, WO/2007/132221, WO/2007/132228. The claims make it look like the morpholine.

Posted in Ariad, bcr abl, Cyclacel, GSK, Plk1, Rho, Vertex | 4 Comments »

VX-680, VX-667: Done

Posted by kinasepro on November 21, 2007

VX-680 halted as:

one patient experienced QTc prolongation.


and the follow-on, VX-667:

Failed to meet pharmacokinetic objectives in a Phase 1 trial

Posted in Aurora, Merck & Co., Vertex | 15 Comments »


Posted by kinasepro on September 15, 2007

Vertex’s Ph2 p38 inhibitor:


is described in WO/2007/103468; model below

Read the rest of this entry »

Posted in p38, Vertex | 24 Comments »

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.


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.

Read the rest of this entry »

Posted in c-Met, Vertex | 6 Comments »

The Vertex J Med Chem

Posted by kinasepro on February 18, 2007

TM brought it up… So here’s my two cents on the latest Vertex J Med Chem.

TM thinks the pyrrol – pyrazoles are ubiquitous, and Vertex says: ‘Kinase activity of pyrazolylpyrroles has been reported previously.16-18′

16:Vertex; WO/2001/057022
17:Vertex; WO/2003/011854
18:Vertex; WO/2003/011855

But refs 16-18 are the apps which cover this series and that’s about it for the 3 pyrroles. The 2-pyrrole substructure can be seen all over the place from things like the DNA/Roche aurora indoles, to chk1, to plenty of others. A subtle difference, but all the difference given how these hit the ERK hinge.

Anyhow, in going after the ERK gatekeeper with the pyrrole, it is surprising to find JNK3 activity since the JNK gatekeeper is methionine rather then glutamine. Interestingly the ligand adopts a flipped conformation in JNK3 more reminiscent of what you’d expect from the pyrrol-2-yl-pyrazole, like indoles, benzimidazoles and such.


The way the paper is worded it seems as though the selectivity was worked out in advance of the structures being obtained. Heh.  If nothing else, the PDB’s give a good example of a pyrrole tightly hydrogen bound to GLN. 2OJG, 2OJI, 2OJJ, 2OK1,

Posted in ERK, Vertex | Leave a Comment »


Posted by kinasepro on January 10, 2007

Vertex has a series of Jak / Rock inhibitors… Of the 31 examples, this one looks somewhat selective for Jak3


fw 213.8 Ki < 500 nM

Thats ridiculous – I love it

Posted in JAK, Vertex | 1 Comment »


Posted by kinasepro on December 12, 2006

Oh wait I’m sorry Merck. My bad, I didn’t realize we’re calling it MK-0457 now. heh… Phase 1 update presented yesterday. The compound hits Aurora, JAK2, Abl etc. etc. and the current study is in ph1 for colorectal cancer. Looks good.

We’ve talked about the compound before here.

Posted in Aurora, clinical, Merck & Co., Vertex | Leave a Comment »

BMS-354825 vs. VX-680

Posted by kinasepro on November 24, 2006

At least the PDB gave us something to look at a few days ago. Here’s a super-cool alignment of dasatinib in Abl to VX-680 in an abl mutant.

Posted in Aurora, bcr abl, BMS, Vertex | Leave a Comment »


Posted by kinasepro on November 20, 2006

Hey Vertex, Interesting Aurora 2,3 inhibitors. I see these come from a series you’ve been on for a while (WO2006058074, WO2005095400). VX680 backups? Hard to tell with how many apps you guys publish. Interesting compounds anyhow.

App includes the pyrazolopyrazines, a core which Roche used first for p38 inhibitors a while back (US2005197340). 1UNG may give a clue to how these are binding.

Posted in Aurora, Vertex | Leave a Comment »


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

Posted in CDK2, JAK, Vertex | Leave a Comment »