PDB Update

2J5E EGF w/ irreversible inhibitor
2J5F EGF w/ irreversible inhibitor
2HWP SRC (cystine mutant)
2HWO SRC (cystine mutant)

2JFL STE-20 like
2JFM STE-20 like
2O0U JNK3
2O2U JNK3
2OF2 LCK
2OF4 LCK
2OFU LCK
2OFV LCK
2OG8 LCK

WO/2007/019884

Roche’s got a Vegf/FGF app in WO/2007/019884

They’ve been around since ’05 though

Who’s in CA?

No, not Canada, A? SF, CA – Here, have a sequal to the Prague entry: This is what you’re missing at YawnFest ’07, err I mean: the MMTC:

Wyeth talks Src/Abl: SKI-606 (American Cyanamid: WO/2000/018740)

Roche talks P38: R1487

And a former Abbot guy is talkinig LCK: A-770041

all great compounds and yadda yadda, just having a hard time seeing anything new here.

AP24534 In here?

Everyone looking at Abl these days is trying to wiggle their way around T315 and Ariad’s latest go is described in the app: WO/2007/021937 with a series of styrene-purines. They look to be a follow-on series to the earlier purine stuff described elsewhere.

Structures for their two previous SRC/ABL leads: AP23464 and AP23451 were disclosed but afaik AP24534 has not.

Beer Cures Cancer!

Sure the story‘s been around a while, but you know why we’re 18 months late covering it:

App is in a Metaproteomics‘ doublet: US20070042063 / WO/2007/021694

This has to be the best application KP has ever seen.

E.V.A.R.

The Thursday List

US20070043068 SGX Pharmaceuticals
US20070043065 p38 AstraZeneca
US20070043063 JAK Vertex
US20070043053 p38 BMS
US20070043048 IKK NOVARTIS
US20070043045 CDK-2 Schering-Plough
US20070043040 Akt Eli Lilly
US20070043010 EGFR AstraZeneca
US20070043009 EGFR AstraZene
US20070043001 AKT Merck
US20070042063 Metaproteomics

WO/2007/022529 Mek Array
WO/2007/022384 Aurora Vertex
WO/2007/022380 Lck / C-Kit AMGEN
WO/2007/022529 Mek1 Array
WO/2007/019884 Vegf / FGF Roche
WO/2007/019933 Met Merck DE
WO/2007/020388 Astrazeneca
WO/2007/020411 Astrazeneca
WO/2007/021710 P38 Merck
WO/2007/021795 Novartis
WO/2007/021694 Metaproteomics
WO/2007/022258 CDK2 Schering-Plough
WO/2007/022268 Novartis / Scripps
WO/2007/021937 Ariad
WO/2007/022241 CDK2 Schering-Plough
WO/2007/022102 Aurora Genentech / Roche
WO/2007/019884 Vegf / Fgf Roche

What’s this I hear?

Is that the sweet sound of Kinase-Blogging Whistling in the Wind? Why yes, yes indeed it is.  (link to the original KP entry)

AZ’s got TrkA

I haven’t read it, but Cephalon’s got an Expert Opinion on the Array Biopharma / AstraZeneca’s Trk-A applications: WO06087538, WO06087530

In the series there’s also: WO/2006/082392

Cephalon’s got a staurosporine analog CEP-701 that hits the kinome, err I mean Vegfr-2, FLT-3, Trk-A and JAK-2 in ph3 trials for AML.

Bonus Link: Multi-Targeted Therapy = nice site.

Amgen ‘n’ IRAK-4

Irak-4? Yah I never heard of it either, but the IRAKs appear to be immunology targets for which Amgen is way out in front. They’ve got a nice paper in Structure, a Biorg. Med. Chem. Lett., and 2 PDB’s: 2NRU, 2NRY.

At first look I was mesmerized by the tyrosine gatekeeper but a second glance on looking over the recent CIP: US20070037803 shows something interesting.

they suggest as much in the BMCL.

The Vertex J Med Chem

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,